Hydroxamates as therapeutic agents

ABSTRACT

The present invention is directed to certain hydroxamate derivatives that are useful in the treatment of hepatitis C. These compounds are also inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.

CROSS-REFERENCE

This application is a divisional patent application of U.S. patentapplication Ser. No. 10/818,755, filed Apr. 6, 2004 now U.S. Pat. No.7,276,612 , which claims priority under 35 U.S.C. 119(e) to U.S.Provisional Application Ser. Nos. 60/461,286 and 60/464,448, filed onApr. 7, 2003, and Apr. 21, 2003, respectively. The disclosures of theseapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention is directed to certain hydroxamate derivativesthat are useful in the treatment of hepatitis C. These compounds arealso inhibitors of histone deacetylase and are therefore useful in thetreatment of diseases associated with histone deacetylase activity.Pharmaceutical compositions and processes for preparing these compoundsare also disclosed.

STATE OF THE ART

Hepatitis C:

Chronic hepatitis C is a slowly progressive disease having a significantimpact on morbidity and mortality. While many patients who contracthepatitis C will have sub clinical or mild disease, at least 80% of theindividuals who contract HCV develop chronic infection and hepatitis.Twenty to fifty percent of these eventually progress to cirrhosis and1-2% develop liver cancer (Hoofnagle, J. H.; 1997; Hepatology 26:15S-20S). There are an estimated 170 million HCV carriers world-wide,and HCV-associated end-stage liver disease is now one of the leadingcause of liver transplantation. In the United States alone, hepatitis Cis responsible for 8,000 to 10,000 deaths annually.

At the present time, interferon-α2b/ribavirin combination therapy is theonly available treatment. Sustained virologic response toIFN-α2b-ribavirin combination therapy occurs in about 40-45% of thosetreated. For those patients who fail interferon-α2b/ribavirincombination therapy, there is currently no alternative to prevent theprogression of liver disease. Thus, a need exists for alternativetherapies for the treatment of chronic HCV infection. The presentinvention fulfills this need.

Histone Deacetylases:

Interest in histone deacetylase enzymes (HDACs) as targets forpharmaceutical development has centered on the role of HDACs inregulating genes associated with cell-cycle progression and thedevelopment and progression of cancer (reviewed in Kramer et. al. 2001.Trends Endocrinol. Metab. 12:294-300). Several studies have shown thattreatment of various cell lines with HDAC inhibitors leads to hyperacetylation of histone proteins and cell-cycle arrest in late G₁ phaseor at the G₂/M transition. Genes involved in the cell cycle that havebeen shown to be up regulated by HDAC inhibitors include p21, p27, p53and cyclin E. Cyclin A and cyclin D have been reported to be downregulated by HDAC inhibitors. In tumor cell lines, several studies haveshown that treatment with HDAC inhibitors can lead to growth inhibition,growth arrest, terminal differentiation and/or apoptosis. In vivostudies have demonstrated growth inhibition of tumors and a reduction intumor metastasis as a result of treatment with HDAC inhibitors.

The clearest link between abnormal HDAC activity and cancer occurs inacute promyelocytic leukemia. In this condition, a chromosomaltranslocation leads to the fusion of the retinoic acid receptor RARαwith the promyelocytic leukemia (PML) or promyelocytic leukemiazinc-finger (PLZF) proteins. Both PML-RARα and PLZF-RARα promote theprogression of leukemia by repressing retinoic acid-regulated genesthrough the abnormal recruitment of SMRT-mSin3-HDAC complex (Lin et.al., 1998, Nature 391:811-814; Grignani et al., 1998, Nature391:815-818). Whereas the PML-RARα form of the disease is treatable withretinoic acid, the PLZF-RARα form is resistant to this treatment. For apatient with the retinoic acid-resistant form of the disease, theaddition of the HDAC inhibitor sodium butyrate to the dosing regimen ledto complete clinical and cytogenic remission (Warrell et al., 1998, J.Natl. Cancer. Inst. 90:1621-1625). HDACs have also been associated withHuntington's disease (Steffan, et al., Nature 413:739-744, “Histonedeacetylase inhibitors arrest polyglutamine-dependent neurodegenerationin Drosophila”).

In summary, an increase in HDAC activity contributes to the pathologyand/or symptomatology of a number of diseases. Accordingly, moleculesthat inhibit the activity of HDAC are useful as therapeutic agents inthe treatment of such diseases.

SUMMARY OF THE INVENTION

In a first aspect, this invention provides a compound of Formula (I):

wherein:

R¹ is hydrogen or alkyl;

X is —O—, —NR²—, or —S(O)_(n) where n is 0-2 and R² is hydrogen oralkyl;

Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionallysubstituted phenylalkylthio, optionally substituted phenylalkylsulfonyl,hydroxy, or optionally substituted phenoxy;

Ar¹ is phenylene or heteroarylene wherein said Ar¹ is optionallysubstituted with one or two groups independently selected from alkyl,halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;

R³ is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl;and

Ar² is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl; or a pharmaceutically acceptable salt thereof.

In a second aspect, this invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) or pharmaceutically acceptable salts thereof and apharmaceutically acceptable excipient.

In a third aspect, this invention is directed to a method for treating adisease in an animal mediated by HDAC which method comprisesadministering to the animal a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient. Preferably, the disease is a proliferativedisorder such as cancer and bipolar disorders and the animal is a human.Preferably, the cancer is prostate cancer, breast cancer, lung melanoma,stomach cancer, neuroblastoma, colon cancer, pancreatic cancer, ovariancancer, T-cell lymphoma, or leukemia such as myelogenous leukemia (MM)and acute myelogenous leukemia (AML).

In a fourth aspect, this invention is directed to a method for treatingcancer in an animal which method comprises administering to the animal apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula (I) or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable excipient in combination withradiation therapy and optionally in combination with one or morecompound(s) independently selected from an estrogen receptor modulator,an androgen receptor modulator, a retinoid receptor modulator, acytotoxic agent, another antiproliferative agent, a prenyl-proteintransferase inhibitor, an HMG-CoA reductase inhibitor, an HIV proteaseinhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor,or a DNA methyl transferase inhibitor.

Applicants have also discovered that the compounds of the presentinvention are useful in the treatment of hepatitis C. Accordingly, in afifth aspect, this invention is directed to a method of treatinghepatitis C in an animal comprising administering the animal apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula (I) or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable excipient optionally incombination with one or more other hepatitis C agent. Preferably, thehepatitis C agents are interferon-α2b, ribavirin, and hcv polymeraseinhibitors.

In a sixth aspect, this invention is direct to an intermediate ofFormula (II):

where R⁵⁰ is hydrogen or alkyl and Ar¹, Ar², R³, X and Y are as definedfor compounds of Formula (I) above; or a salt thereof. Preferably, Ar¹,Ar², R³, X and Y are as defined in Preferred embodiments below.

In a seventh aspect, this invention is directed to a process ofpreparing a compound of Formula (I) comprising:

(i) reacting a compound of Formula (III):

were R⁵¹ is hydroxy, alkoxy, halo, or succinimido ester with ahydroxylamine of formula NH₂OR″ where R″ is hydrogen, alkyl, or anoxygen protecting group; or

(ii) treating a compound of Formula (IV):

where M⁺ is an alkali metal with an acid; followed by treatment withNH₂OR″ where R″ is hydrogen, alkyl, or an oxygen protecting group;

to give a compound of Formula (V):

(iii) optionally removing R″ group in compound (V) to give a compound ofFormula (I) where R¹ is hydrogen;

(iv) optionally forming an acid addition salt of the product formed inStep (i), (ii), or (iii) above;

(v) optionally forming free base of the product formed in Step (i),(ii), (iii), or (iv) above; or

(vi) optionally modifying any of the X, Y, R¹, R², R³, Ar¹ and Ar²groups in the product formed in Step (i), (ii), (iii), (iv), or (v)above.

In a eighth aspect, this invention is directed to the use of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of cancer.

In a ninth aspect, this invention is directed to the use of a compoundof Formula (I) or (II) or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for the treatment of hepatitis C.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meaning:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), pentyl (including allisomeric forms), and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms unless otherwise stated e.g., methylene,ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene,pentylene, and the like.

“Alkenylene” means a linear divalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms containing one or two double bonds, e.g., ethenylene,propenylene, 2-propenylene, butenylene (including all isomeric forms),and the like.

“Alkylthio” means a —SR radical where R is alkyl as defined above, e.g.,methylthio, ethylthio, propylthio (including all isomeric forms),butylthio (including all isomeric forms), and the like.

“Alkylsulfinyl” means a —S(O)R radical where R is alkyl as definedabove, e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl (includingall isomeric forms), and the like.

“Alkylsulfonyl” means a —SO₂R radical where R is alkyl as defined above,e.g., methylsulfonyl, ethylsulfonyl, and the like.

“Amino” means a —NH₂; or an N-oxide derivative or a protected derivativethereof e.g., —NH→O, —NHBoc, —NHCbz, and the like. Preferably, —NH₂.

“Alkylamino” means a —NHR radical where R is alkyl as defined above; oran N-oxide derivative, or a protected derivative thereof, e.g.,methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino,methylamino-N-oxide, —N(Boc)CH₃, and the like.

“Alkoxy” means a —OR radical where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, andthe like.

“Alkoxycarbonyl” means a —C(O)OR radical where R is alkyl as definedabove, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with at least one alkoxy group, preferablyone or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-,2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

“Alkoxyalkyloxy” means a —OR radical where R is alkoxyalkyl as definedabove, e.g., methoxyethoxy, 2-ethoxyethoxy, and the like.

“Alkoxyalkyloxyalkyl” means -(alkylene)-R radical where R isalkoxyalkyloxy as defined above, e.g., methoxyethoxymethyl,2-ethoxyethoxymethyl, and the like.

“Aminoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with at least one, preferably one or two, —NRR′where R is hydrogen, alkyl, or —COR^(a) where R^(a) is alkyl, and R′ isselected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, optionallysubstituted phenyl, optionally substituted phenylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyl, orhaloalkyl; or an N-oxide derivative or a protected derivative thereof.Preferably, R and R′ are independently selected from hydrogen, alkyl, or—COR^(a) where R^(a) is alkyl; or an N-oxide derivative, or a protectedderivative e.g., aminomethyl, methylaminoethyl,2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl,diethylaminoethyl, acetylaminopropyl, aminomethyl-N-oxide, and the like.

“Aminoalkoxy” means a —OR radical where R is aminoalkyl as definedabove, e.g., 2-aminoethoxy, 2-dimethylaminopropoxy, and the like.

“Aminocarbonyl” means a —CONRR radical where each R is independentlyhydrogen or alkyl as defined above, e.g., —CONH₂, methylaminocarbonyl,2-dimethylaminocarbonyl, and the like.

“Acylamino” means a —NHCOR radical where R is alkyl as defined above,e.g., acetylamino, propionylamino, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 12 ring atoms e.g., phenyl, naphthyl or anthracenyl.Unless stated otherwise, the aryl ring is optionally substituted withone, two, or three substituents independently selected from alkyl,alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino,hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl,alkoxyalkyloxyalkyl, optionally substituted phenyl, optionallysubstituted phenylalkyl, optionally substituted heteroaryl,cycloalkyloxy, cycloalkenyloxy, optionally substitutedphenylcarbonylamino, optionally substituted heteroaryloxy, optionallysubstituted heteroaralkyloxy, aminoalkyl, aminoalkoxy, alkoxyalkyl,alkoxyalkyloxy, methylenedioxy, haloalkoxyalkyl, optionally substitutedphenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted heterocycloalkyl, optionally substitutedheterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl,optionally substituted heterocycloalkylalkyloxy, optionally substitutedheterocycloalkyloxy, -alkylene-S(O)_(n)—R^(a) (where n is 0 to 2 andR^(a) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, optionallysubstituted phenyl, optionally substituted phenylalkyl, optionallysubstituted heteroaryl, or optionally substituted heteroaralkyl),-alkylene-NHSO₂—R^(b) (where R^(b) is alkyl, haloalkyl, optionallysubstituted phenyl, optionally substituted phenylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyl, oroptionally substituted heterocycloalkyl), -alkylene-NHCO—R^(c) (whereR^(c) is alkyl, haloalkyl, optionally substituted phenyl, optionallysubstituted phenylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, or optionally substituted heterocycloalkyl),or -(alkylene)n1-CONR^(d)R^(e) (where n1 is 0 or 1, R^(d) and R^(e) areindependently, hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, optionally substituted phenyl, optionally substitutedphenylalkyl, optionally substituted heteroaryl, optionally substitutedheteroaralkyl, or optionally substituted heterocycloalkylalkyl, or R^(d)and R^(e) together with the nitrogen atom to which they are attachedform heterocycloalkyl) wherein the alkyl chain in haloalkoxyalkyl,optionally substituted phenyloxyalkyl, optionally substitutedheteroaryloxyalkyl, or aminoalkyl is optionally substituted with one ortwo fluoro. Preferably, the substituents are independently methoxy,methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy,2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy,2-(N,N-dimethylamino)-ethoxy, methoxymethyl, phenoxymethyl,2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N,N-dimethylaminomethyl,i-propoxymethyl, or phenoxymethyl.

“Aralkyl” means -(alkylene)-R radical where R is aryl as defined above.

“Aralkenyl” means -(alkenylene)-R radical where R is aryl as definedabove.

“Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical ofthree to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or adamantyl. The cycloalkyl is optionally substituted withoptionally substituted phenyl.

“Cycloalkenyl” means a cyclic unsaturated monovalent hydrocarbon radicalof three to six carbon atoms, e.g., cyclopropenyl, cyclobutenyl,cyclohexenyl, and the like.

“Cycloalkylalkyl” means a -(alkylene)-R radical where R is cycloalkyl asdefined above; e.g., cyclopropylmethyl, cyclobutylmethyl,cyclopentylethyl, or cyclohexylmethyl, and the like.

“Cycloalkyloxy” means a —OR radical where R is cycloalkyl as definedabove, e.g., cyclopropyloxy, cyclohexyloxy, and the like.

“Cycloalkenyloxy” means a —OR radical where R is cycloalkenyl as definedabove, e.g., cyclopropenyloxy, cyclohexenyloxy, and the like.

“Dialkylamino” means a —NRR′ radical where R and R′ are independentlyalkyl as defined above, e.g., dimethylamino, diethylamino,methylpropylamino, methylethylamino, n-, iso-, or tert-butylamino, andthe like.

“Halo” means fluoro, chloro, bromo, and iodo, preferably fluoro orchloro.

“Haloalkyl” means alkyl substituted with one or more halogen atoms,preferably one to five halogen atoms, preferably fluorine or chlorine,including those substituted with different halogens, e.g., —CH₂Cl, —CF₃,—CHF₂, —CF₂CF₃, —CF(CH₃)₃, and the like.

“Haloalkoxy” means a —OR radical where R is haloalkyl as defined abovee.g., —OCF₃, —OCHF₂, and the like.

“Haloalkoxyalkyl” means a -(alkylene)-OR radical where R is haloalkyl asdefined above e.g., trifluoromethyloxymethyl,2,2,2-trifluoroethyloxymethyl, 2-trifluoromethoxyethyl, and the like.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one or two hydroxy groups, provided thatif two hydroxy groups are present they are not both on the same carbonatom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Hydroxyalkoxy” or “hydroxyalkyloxy” means a —OR radical where R ishydroxyalkyl as defined above.

“Hydroxyalkoxyalkyl” or “hydroxyalkyloxyalkyl” means -(alkylene)-ORradical where R is hydroxyalkyl as defined above e.g.,hydroxymethyloxymethyl, hydroxyethyloxymethyl, and the like.

“Heterocycloalkyl” means a saturated or unsaturated monovalent cyclicgroup of 3 to 8 ring atoms in which one or two ring atoms are heteroatomselected from N, O, or S(O)_(n), where n is an integer from 0 to 2, theremaining ring atoms being C. One or two ring carbon atoms canoptionally be replaced by a —CO— group. More specifically the termheterocycloalkyl includes, but is not limited to, pyrrolidino,piperidino, morpholino, piperazino, tetrahydropyranyl,tetrahydroquinolinyl and thiomorpholino, and the derivatives thereof(formed when the heterocyloalkyl ring is substituted with a substituentlisted below); and an N-oxide or a protected derivative thereof. Theheterocycloalkyl is optionally fused to aryl. Unless stated otherwise,the heterocyloalkyl ring is optionally substituted with one, two, orthree substituents independently selected from alkyl, alkoxy, halo,haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy,hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl,optionally substituted phenyl, optionally substituted phenylalkyl,cycloalkyloxy, cycloalkenyloxy, optionally substitutedphenylcarbonylamino, optionally substituted heteroaryl, optionallysubstituted heteroaralkyloxy, aminoalkyl, aminoalkoxy, alkoxyalkyl,alkoxyalkyloxy, methylenedioxy, haloalkoxyalkyl, optionally substitutedphenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted heterocycloalkyloxyalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy,optionally substituted heterocycloalkyloxy, -alkylene-S(O)_(n)—R^(a)(where n is 0 to 2 and R^(a) is alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, optionally substituted phenyl, optionally substitutedphenylalkyl, optionally substituted heteroaryl, or optionallysubstituted heteroaralkyl), -alkylene-NHSO₂—R^(b) (where R^(b) is alkyl,haloalkyl, optionally substituted phenyl, optionally substitutedphenylalkyl, optionally substituted heteroaryl, or optionallysubstituted heteroaralkyl), -alkylene-NHCO—R^(c) (where R^(c) is alkyl,haloalkyl, optionally substituted phenyl, optionally substitutedphenylalkyl, optionally substituted heteroaryl, or optionallysubstituted heteroaralkyl), or -(alkylene)n1-CONR^(d)R^(e) (where n1 is0 or 1, R^(d) and R^(e) are independently, hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl,optionally substituted phenylalkyl, optionally substituted heteroaryl,optionally substituted heteroaralkyl, or optionally substitutedheterocycloalkylalkyl, or R^(d) and R^(e) together with the nitrogenatom to which they are attached form heterocycloalkyl) wherein the alkylchain in haloalkoxyalkyl, optionally substituted phenyloxyalkyl,optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionallysubstituted with one or two fluoro. Preferably, the substituents areindependently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro,2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy,2-hydroxyethoxy, 2-(N,N-dimethylamino)ethoxy, methoxymethyl,phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl,N,N-dimethylaminomethyl, i-propoxymethyl, or phenoxymethyl.

“Heterocycloalkylalkyl” means -(alkylene)-R radical where R isheterocycloalkyl ring as defined above e.g., furanylmethyl,piperazinylmethyl, morpholinylethyl, and the like.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms where one or more, preferably one, two, or three,ring atoms are heteroatom selected from N, O, or S, the remaining ringatoms being carbon. More specifically the term heteroaryl includes, butis not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl,indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,isoxazolyl, benzoxazolyl, benzothiophenyl, benzthiazolyl, quinolinyl,isoquinolinyl, benzofuranyl, benzopyranyl, and thiazolyl, and thederivatives thereof (formed when the heterocyloalkyl ring is substitutedwith a substituent listed below); or an N-oxide or a protectedderivative thereof. Unless stated otherwise, the heteroaryl ring isoptionally substituted with one, two, or three substituentsindependently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy,amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy,hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionally substituted phenyl,cycloalkyloxy, cycloalkenyloxy, optionally substitutedphenylcarbonylamino, optionally substituted heteroaryl, optionallysubstituted heteroaryloxy, optionally substituted heteroaralkyloxy,aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy,haloalkoxyalkyl, optionally substituted phenylalkyl, optionallysubstituted phenyloxy, optionally substituted phenylalkyloxy, optionallysubstituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl,optionally substituted heterocycloalkyloxyalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy,optionally substituted heterocycloalkyloxy, -alkylene-S(O)_(n)—R^(a)(where n is 0 to 2 and R^(a) is alkyl, hydroxyalkyl, haloalkyl,optionally substituted phenyl, optionally substituted phenylalkyl,optionally substituted heteroaryl, or optionally substitutedheteroaralkyl), -alkylene-NHSO₂—R^(b) (where R^(b) is alkyl, haloalkyl,optionally substituted phenyl, optionally substituted phenylalkyl,optionally substituted heteroaryl, optionally substituted heteroaralkyl,or optionally substituted heterocycloalkyl), -alkylene-NHCO—R^(c) (whereR^(c) is alkyl, haloalkyl, hydroxyl, optionally substituted phenyl,optionally substituted phenylalkyl, optionally substituted heteroaryl,optionally substituted heteroaralkyl, or optionally substitutedheterocycloalkyl), -(alkylene)n1-CONR^(d)R^(f) (where n1 is 0 or 1,R^(d) is hydrogen or alkyl, and R^(f) is hydrogen, alkyl, hydroxylalkyl,alkoxyalkyl, optionally substituted phenyl, optionally substitutedphenylalkyl, optionally substituted heteroaryl, optionally substitutedheteroaralkyl, or optionally substituted heterocycloalkylalkyl, or R^(d)and R^(f) together with the nitrogen atom to which they are attachedform heterocycloalkyl), -alkylene-NR^(e)-alkyleneCONR^(c)R^(d) (whereR^(c) is as defined above and R^(d) and R^(e) are independently hydrogenor alkyl), or carboxyalkylaminoalkyl wherein the alkyl chain inhaloalkoxyalkyl, optionally substituted phenyloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or aminoalkyl is optionally substitutedwith one or two fluoro. Preferably, the substituents are independentlymethoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro,2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy,2-hydroxyethoxy, 2-(N,N-dimethylamino)ethoxy, methoxymethyl,phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl,N,N-dimethylaminomethyl, i-propoxymethyl, or phenoxymethyl.

When the heteroaryl ring is divalent it has been referred to asheteroarylene in this application.

“Heteroarylamino” means a NHR radical where R is heteroaryl as definedabove.

“Heteroaralkyl” means a -(alkylene)-R radical where R is heteroaryl asdefined above.

“Heteroaralkenyl” means -(alkenylene)-R radical where R is heteroaryl asdefined above.

“Methylenedioxy” means —O—CH₂—O—.

The present invention also includes the prodrugs of compounds of Formula(I). The term prodrug is intended to represent covalently bondedcarriers, which are capable of releasing the active ingredient ofFormula (I) when the prodrug is administered to a mammalian subject.Release of the active ingredient occurs in vivo. Prodrugs can beprepared by techniques known to one skilled in the art. These techniquesgenerally modify appropriate functional groups in a given compound.These modified functional groups however regenerate original functionalgroups by routine manipulation or in vivo. Prodrugs of compounds ofFormula (I) include compounds wherein a hydroxy, amino, carboxylic, or asimilar group is modified. Examples of prodrugs include, but are notlimited to esters (e.g., acetate, formate, and benzoate derivatives),carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy or aminofunctional groups in compounds of Formula (I)), amides (e.g.,trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugsof compounds of Formula (I) are also within the scope of this invention.

The present invention also includes N-oxide derivatives and protectedderivatives of compounds of Formula (I). For example, when compounds ofFormula (I) contain an oxidizable nitrogen atom, the nitrogen atom canbe converted to an N-oxide by methods well known in the art. Whencompounds of Formula (I) contain groups such as hydroxy, carboxy, thiolor any group containing a nitrogen atom(s), these groups can beprotected with a suitable protecting groups. A comprehensive list ofsuitable protective groups can be found in T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc. 1981, thedisclosure of which is incorporated herein by reference in its entirety.The protected derivatives of compounds of Formula (I) can be prepared bymethods well known in the art.

“Phenylene” means a divalent phenyl radical.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. It is understood that thepharmaceutically acceptable salts are non-toxic. Additional informationon suitable pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, which is incorporated herein by reference.

The compounds of the present invention may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of materials. All chiral, diastereomeric, racemic formsare within the scope of this invention, unless the specificstereochemistry or isomeric form is specifically indicated.

Certain compounds of Formula (I) can exist as tautomers and/or geometricisomers. All possible tautomers and cis and trans isomers, individualand mixtures thereof are within the scope of this invention.Additionally, as used herein the terms alkyl includes all the possibleisomeric forms of said alkyl group albeit only a few examples are setforth. Furthermore, when the cyclic groups such as aryl, heteroaryl,heterocycloalkyl are substituted, they include all the positionalisomers albeit only a few examples are set forth. Furthermore, allpolymorphic forms and hydrates of a compound of Formula (I) are withinthe scope of this invention.

“Optionally substituted phenyl” means a phenyl ring optionallysubstituted with one, two, or three substituents independently selectedfrom alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, heteroaryl(that is optionally substituted with one or two substituentsindependently selected from alkyl, halo, hydroxy, alkoxy, carboxy,amino, alkylamino, or dialkylamino), heterocycloalkyl (that isoptionally substituted with one or two substituents independentlyselected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino,or dialkylamino), amino, alkylamino, dialkylamino, hydroxy, cyano,nitro, methylenedioxy, aminocarbonyl, acylamino, hydroxyalkyl,alkoxycarbonyl, aminoalkyl, or carboxy or optionally substituted withfive fluorine atoms. When the phenyl is substituted it is referredherein as “substituted phenyl”.

“Optionally substituted phenyloxy or phenoxy” means a —OR radical whereR is optionally substituted phenyl as defined above e.g., phenoxy,chlorophenoxy, and the like.

“Optionally substituted phenylcarbonylamino” means a —NHCOR radicalwhere R is optionally substituted phenyl as defined above e.g.,benzoylamino, and the like.

“Optionally substituted phenylalkyl” means -(alkylene)-R radical where Ris optionally substituted phenyl as defined above e.g., benzyl,phenylethyl, and the like.

“Optionally substituted phenylalkyloxy” means a —OR radical where R isoptionally substituted phenylalkyl as defined above e.g., benzyloxy,phenylethyloxy, and the like.

“Optionally substituted phenylalkylthio” means a —S-(alkylene)-R radicalwhere R is optionally substituted phenyl as defined above e.g.,benzylthio, phenylethylthio, and the like.

“Optionally substituted phenylalkylsulfonyl” means a —SO₂— (alkylene)-Rradical where R is optionally substituted phenyl as defined above e.g.,benzylsulfonyl, phenylethylsulfonyl, and the like.

“Optionally substituted phenylalkenyl” means -(alkenylene)-R radicalwhere R is optionally substituted as defined above e.g., phenylethenyl,phenylpropenyl, and the like.

“Optionally substituted phenoxyalkyl” means a -(alkylene)-OR radicalwhere R is optionally substituted phenyl as defined above e.g.,phenoxymethyl, phenoxyethyl, and the like.

“Optionally substituted heteroaryl” means a monovalent monocyclic orbicyclic aromatic radical of 5 to 10 ring atoms where one or more,preferably one, two, or three, ring atoms are heteroatoms selected fromN, O, or S, the remaining ring atoms being carbon that is optionallysubstituted with one, two, or three substituents independently selectedfrom alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino,dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl,alkoxycarbonyl, aminoalkyl, optionally substituted phenyl, optionallysubstituted phenoxy, carboxy, or heteroaryl that is optionallysubstituted with alkyl, halo, hydroxy, alkoxy, carboxy, amino,alkylamino, or dialkylamino, heterocycloalkyl optionally substitutedwith one or two substituents independently selected from alkyl, halo,hydroxy, alkoxy, amino, alkylamino or dialkylamino,heterocycloalkylalkyl optionally substituted with one or twosubstituents independently selected from alkyl, halo, hydroxy, alkoxy,amino, alkylamino or dialkylamino, or heteroarylamino optionallysubstituted with one or two substituents independently selected fromalkyl, halo, hydroxy, alkoxy, amino, alkylamino or dialkylamino. Morespecifically the term optionally substituted heteroaryl includes, but isnot limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl,indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, andthiazolyl, and the derivatives thereof (formed when the heteroaryl ringis substituted with a substituent listed above); or an N-oxide or aprotected derivative thereof.

“Optionally substituted heteroaryloxy” means a —OR radical where R isoptionally substituted heteroaryl as defined above e.g., furanyloxy,pyridinyloxy, and the like.

“Optionally substituted heteroaralkyloxy” means a —OR radical where R isoptionally substituted heteroaralkyl ring as defined below.

“Optionally substituted heteroaryloxyalkyl” means a -(alkylene)-ORradical where R is optionally substituted heteroaryl ring as definedabove.

“Optionally substituted heteroaralkyl” means -(alkylene)-R radical whereR is optionally substituted heteroaryl ring as defined above.

“Optionally substituted heterocycloalkyl” means a saturated orunsaturated monovalent cyclic group of 3 to 8 ring atoms in which one ortwo ring atoms are heteroatoms selected from N, O, or S(O)_(n), where nis an integer from 0 to 2, the remaining ring atoms being C. One or tworing carbon atoms can optionally be replaced by a —CO— group. Morespecifically the term heterocycloalkyl includes, but is not limited to,pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, andthiomorpholino and the derivatives thereof (formed when theheterocycloalkyl ring is substituted with a substituent listed below);or an N-oxide or a protected derivative thereof. The heterocycloalkyl isoptionally fused to aryl and is optionally substituted with one, two, orthree substituents independently selected from alkyl, cycloalkyl, halo,alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy,cyano, nitro, optionally substituted phenylalkyl, optionally substitutedheteroaralkyl aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl,or carboxy.

“Optionally substituted heterocycloalkyloxy” means a —OR radical where Ris optionally substituted heterocycloalkyl ring as defined above.

“Optionally substituted heterocycloalkylalkyl” means -(alkylene)-Rradical where R is optionally substituted heterocycloalkyl ring asdefined above.

“Optionally substituted heterocycloalkylalkyloxy” means a —OR radicalwhere R is optionally substituted heterocycloalkylalkyl ring as definedabove.

“Optionally substituted heterocycloalkyloxyalkyl” means -(alkylene)-ORradical where R is optionally substituted heterocycloalkyl as definedabove e.g., piperidinyloxymethyl, pyrrolidinyloxyethyl, and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocycloalkyl group optionallymono- or di-substituted with an alkyl group” means that the alkyl maybut need not be present, and the description includes situations wherethe heterocycloalkyl group is mono- or disubstituted with an alkyl groupand situations where the heterocycloalkyl group is not substituted withthe alkyl group.

A “pharmaceutically acceptable carrier or excipient” means a carrier oran excipient that is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes a carrier or an excipient that is acceptablefor veterinary use as well as human pharmaceutical use. “Apharmaceutically acceptable carrier/excipient” as used in thespecification and claims includes both one and more than one suchexcipient.

“Treating” or “treatment” of a disease includes:

(i) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease;

(ii) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms; or

(iii) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

A “therapeutically effective amount” means the amount of a compound ofFormula (I) that, when administered to a mammal for treating a disease,is sufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

Representative compounds of Formula (I) are disclosed in Table I-IVbelow.

Compounds of Formula (I) where R¹ and R³ are hydrogen, Ar¹ is phenyl andAr² and Y are as defined in Table I below are:

TABLE I

Cpd # Ar² Y 1 phenyl —CH₂—CH₂— 2 trans phenyl-CH═CH— —CH₂—CH₂— 3 transphenylcyclopropyl —CH₂—CH₂— 4 trans 4-MeO-phenyl-CH═CH— —CH₂—CH₂— 52-phenylethyl —CH₂—CH₂— 6 1H-indol-3-ylmethyl —CH₂—CH₂— 7 thiophen-2-yl—CH₂—CH₂— 8 pyridin-3-yl —CH₂—CH₂— 9 4-biphenyl —CH₂—CH₂— 10 3-biphenyl—CH₂—CH₂— 11 5-phenylthiophen-2-yl —CH₂—CH₂— 12 thiophen-2-ylmethyl—CH₂—CH₂— 13 naphth-2-yl —CH₂—CH₂— 14 quinolin-6-yl —CH₂—CH₂— 154-phenylthiazol-2-yl —CH₂—CH₂— 16 4-tert-butylphenyl —CH₂—CH₂— 17 transpyridin-3-yl-CH═CH— —CH₂—CH₂— 18 4-pyrrol-1-ylphenyl —CH₂—CH₂— 194-(cyclohexene-3-oxy)-phenyl —CH₂—CH₂— 20 benzothiazol-2-yl —CH₂—CH₂— 21benzoxazol-2-yl —CH₂—CH₂— 22 octahydroisoquinolin-2-ylmethyl —CH₂—CH₂—23 4-pyridin-4-yl-piperazin-1-ylmethyl —CH₂—CH₂— 24 furan-2-yl —CH₂—CH₂—25 4-(pyridin-3-yl)-phenyl —CH₂—CH₂— 26 4-(pyridin-2-yl)-phenyl—CH₂—CH₂— 27 1H-benzimidazol-2-yl —CH₂—CH₂— 28 1H-pyrrol-2-yl —CH₂—CH₂—29 4-(benzoylamino)-phenyl —CH₂—CH₂— 30 4-(pyridin-4-yl)-thiazol-2-yl—CH₂—CH₂— 31 adamantan-1-yl —CH₂—CH₂— 32 2,4-difluorophenyl —CH₂—CH₂— 33trans 3,4-methylenedioxyphenylCH═CH— —CH₂—CH₂— 343,4-methylenedioxyphenyl —CH₂—CH₂— 35 3,4-dimethoxyphenyl —CH₂—CH₂— 363,5-dimethoxyphenyl —CH₂—CH₂— 37 3,4-difluorophenyl —CH₂—CH₂— 382,5-dimethylphenyl —CH₂—CH₂— 39 2,3-dichlorophenyl —CH₂—CH₂— 402,3-dimethylphenyl —CH₂—CH₂— 41 4-chloro-2-methoxyphenyl —CH₂—CH₂— 423-ethoxyphenyl —CH₂—CH₂— 43 4-methoxy-2-methylphenyl —CH₂—CH₂— 443-fluoro-4-methoxyphenyl —CH₂—CH₂— 45 2-(thiophen-2-ylmethoxy)phenyl—CH₂—CH₂— 46 3-(thiophen-2-ylmethoxy)-phenyl —CH₂—CH₂— 47 2-phenylphenyl—CH₂—CH₂— 48 1H-indol-5-yl —CH₂—CH₂— 49 1H-indol-3-yl —CH₂—CH₂— 50quinolin-3-yl —CH₂—CH₂— 51 quinolin-8-yl —CH₂—CH₂— 52 1H-indazol-3-yl—CH₂—CH₂— 53 1H-benzotriazol-5-yl —CH₂—CH₂— 54 isoquinolin-1-yl—CH₂—CH₂— 55 isoquinolin-3-yl —CH₂—CH₂— 56 quinoxalin-2-yl —CH₂—CH₂— 57naphth-1-yl —CH₂—CH₂— 58 quinolin-2-yl —CH₂—CH₂— 59 2-pyrrol-1-yl-phenyl—CH₂—CH₂— 60 4-fluoronaphth-1-yl —CH₂—CH₂— 61 1H-benzimidazol-5-yl—CH₂—CH₂— 62 1-methyl-indol-3-yl —CH₂—CH₂— 63 4-MeO-quinolin-2-yl—CH₂—CH₂— 64 3-MeO-naphth-2-yl —CH₂—CH₂— 65 2-MeO-naphth-1-yl —CH₂—CH₂—66 quinolin-4-yl —CH₂—CH₂— 67 trans phenyl-CH═C(CH₃)— —CH₂—CH₂— 682-N,N-dimethylaminomethylbenzofuran-5-yl —CH₂—CH₂— 69 indolin-1-yl—CH₂—CH₂— 70 1,2,3,4-tetrahydroquinolin-1-yl —CH₂—CH₂— 71 trans5-hydroxybenzofuran-2-yl-C(CH₃)═CH— -(S)-CH(CH₂CH₃)—CH₂— 72 trans5-(1-cyclopropylpiperidin-4- -(S)-CH(CH₂CH₃)—CH₂—yloxy)benzofuran-2-yl-C(CH₃)═CH— 73 benzofuran-2-yl-(S)-CH(2-phenylethyl)-CH₂— 745-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl —CH₂—CH₂— 755-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl -(S)-CH(CH₂CH₃)—CH₂—76 5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl -(R)-CH₂—CH(CH₃)—77 5-[1-(2,2,2-trifluoroethyl)piperidin-4- —CH₂—CH₂—yloxy]benzofuran-2-yl 78 benzofuran-2-yl -(R)-CH(benzylSO₂-methyl)-CH₂—79 benzofuran-2-yl -(R)-CH(benzylS-methyl)-CH₂— 80 trans5-methoxybenzofuran-2-yl-C(CH₃)═CH— —CH₂—CH₂— 811,2,3,4-tetrahydroisoquinolin-2-yl —CH₂—CH₂— 82 isoindolin-2-yl—CH₂—CH₂— 83 morpholin-4-yl —CH₂—CH₂— 84 4-benzyl-piperazin-1-yl—CH₂—CH₂— 85 (R)-3-HO-pyrrolidin-1-yl —CH₂—CH₂— 86 piperidin-1-yl—CH₂—CH₂— 87 6-CH₃-1,2,3,4-tetrahydroquinolin-1-yl —CH₂—CH₂— 882-CH₃-indolin-1-yl —CH₂—CH₂— 896-F-2-CH₃-1,2,3,4-tetrahydroquinolin-1-yl —CH₂—CH₂— 90 isoindolin-1-yl-(S)-CH(CH₂CH₃)—CH₂— 91 trans phenyl-CH═CH— —CH₂—CH₂—CH₂— 92 trans4-CH₃O-phenyl-CH═CH— —CH₂—CH₂—CH₂— 93 4-phenylthiazol-2-yl —CH₂—CH₂—CH₂—94 trans phenyl-CH═CH— -(S)-CH(methyl)-CH₂— 95 trans phenyl-CH═CH—-(R)-CH(methyl)-CH₂— 96 trans phenyl-CH═CH— -(S)-CH(i-butyl)-CH₂— 97trans phenyl-CH═CH— -(S)-CH(cyclohexyl-methyl)-CH₂— 98 transphenyl-CH═CH— -(S)-CH(i-propyl)-CH₂— 99 trans phenyl-CH═CH—-(S)-CH(benzyl)-CH₂— 100 trans phenyl-CH═CH— -(R)-CH(benzyl)-CH₂— 101trans phenyl-CH═CH— -(R)-CH(i-butyl)-CH₂— 102 trans phenyl-CH═CH—-(R)-CH(i-propyl)-CH₂— 103 trans phenyl-CH═CH— -(RS)-CH(n-butyl)-CH₂—104 trans phenyl-CH═CH— -(RS)-CH(4-Cl-benzyl)-CH₂— 105 transphenyl-CH═CH— -(S)-CH(CH₂CH₃)—CH₂— 106 trans phenyl-CH═CH—-(R)-CH(CH₂CH₃)—CH₂— 107 trans phenyl-CH═CH— -(S)-CH(2-MeS-ethyl)-CH₂—108 trans phenyl-CH═CH— -(R)-CH(2-MeS-ethyl)-CH₂— 109 transphenyl-CH═CH— -(S)-CH(phenyl)-CH₂— 110 trans phenyl-CH═CH—-(R)-CH(phenyl)-CH₂— 111 trans phenyl-CH═CH— -(S)-CH(2-MeSO₂-ethyl)-CH₂—112 trans phenyl-CH═CH— -(R)-CH(2-MeSO₂-ethyl)-CH₂— 113 transphenyl-CH═CH— -(R)-CH(benzylSO₂-methyl)-CH₂— 114 thiophen-2-yl-(S)-CH(CH₂CH₃)—CH₂— 115 4-biphenyl -(S)-CH(CH₂CH₃)—CH₂— 116 naphth-2-yl-(S)-CH(CH₂CH₃)—CH₂— 117 trans phenyl-CH═CH—-(R)-CH(benzyl-S-methyl)-CH₂— 118 phenyl -(S)-CH(CH₂CH₃)—CH₂— 119 benzyl-(S)-CH(CH₂CH₃)—CH₂— 120 2-phenylethyl -(S)-CH(CH₂CH₃)—CH₂— 121 transphenyl-CH═CH— -(S)-CH(hydroxy-methyl)-CH₂— 122 4-phenylthiazol-2-yl-(S)-CH(CH₂CH₃)—CH₂— 123 trans 4-CH₃O-phenyl-CH═CH— -(S)-CH(CH₂CH₃)—CH₂—124 2-N,N-dimethylaminomethyl-benzofuran-5-yl- -(S)-CH(CH₂CH₃)—CH₂— 125trans phenyl-CH═CH— -(R)-CH₂—CH(CH₃)— 126 trans phenyl-CH═CH—-(S)-CH₂—CH(CH₃)— 127 4-phenyl-thiazol-2-yl -(R)-CH₂—CH(CH₃)— 1284-phenyl-thiazol-2-yl -(S)-CH₂—CH(CH₃)— 129 4-biphenyl -(R)-CH₂—CH(CH₃)—130 trans 4-CH₃O-phenyl-CH═CH— -(R)-CH₂—CH(CH₃)— 1314-(2-pyridin-4-ylthiazol-5-yl)phenyl —CH₂—CH₂— 1327-chloro-4-methylbenzofuran-2-yl —CH₂—CH₂— 1334-[2-(4-methylpiperazin-1-yl)thiazol-5-yl]- —CH₂—CH₂— phenyl 1344-(2-pyridin-4-ylaminothiazol-5-yl)phenyl —CH₂—CH₂— 1354-(4-methylpiperazin-1-yl)phenyl —CH₂—CH₂— 1364-(4-hydroxypiperidin-1-yl)phenyl —CH₂—CH₂— 1374-(4-morpholin-4-ylmethylthiazol-2-yl)phenyl —CH₂—CH₂— 1387-fluoro-4-methylbenzofuran-2-yl —CH₂—CH₂— 1397-fluoro-4-(2-methoxyethoxymethyl)- —CH₂—CH₂— benzofuran-2-yl 1404-hydroxyquinolin-2-yl —CH₂—CH₂— 1417-fluoro-4-phenoxymethylbenzofuran-2-yl —CH₂—CH₂— 1434-[2-(4-methylpiperazin-1-ylmethyl)thiazol-5- —CH₂—CH₂— yl]phenyl 144pyridin-2-yl —CH₂—CH₂— 145 3-hydroxypyridin-2-yl —CH₂—CH₂— 1466-hydroxypyridin-2-yl —CH₂—CH₂— 147 6-(4-nitrophenoxy)pyridin-2-yl—CH₂—CH₂— 148 4-(2-methoxyethoxy)quinolin-2-yl —CH₂—CH₂— 1494-(2-dimethylaminoethoxy)quinolin-2-yl —CH₂—CH₂— 150 6-bromopyridin-2-yl—CH₂—CH₂— 151 5-bromopyridin-3-yl —CH₂—CH₂— 152 4-methoxyquinolin-2-yl-(S)-CH(CH₂CH₃)—CH₂— 153 1-methoxynaphth-2-yl —CH₂—CH₂— 1544-methoxyquinolin-2-yl -(R)-CH₂—CH(CH₃)— 155 5-phenylpyridin-3-yl—CH₂—CH₂— 156 6-benzyloxypyridin-2-yl —CH₂—CH₂— 1576-(2-methylpropyloxy)pyridin-2-yl —CH₂—CH₂— 1586-(2-phenylethyloxy)pyridin-2-yl —CH₂—CH₂— 1594-(3,3,3-trifluoropropyloxy)quinolin-2-yl —CH₂—CH₂— 1604-(3,3,3-trifluoropropyloxy)quinolin-2-yl -(S)-CH(CH₂CH₃)—CH₂— 1614-(3,3,3-trifluoropropyloxy)quinolin-2-yl -(R)-CH₂—CH(CH₃)— 162 trans3-hydroxyphenyl-CH═CH— —CH₂—CH₂— 163 trans 4-hydroxyphenyl-CH═CH——CH₂—CH₂— 164 3′-(2-hydroxyethyl)biphen-4-yl —CH₂—CH₂— 1653′-(2-hydroxyethyl)biphen-3-yl —CH₂—CH₂— 1662′-(2-hydroxyethyl)biphen-4-yl —CH₂—CH₂— 167 transbenzofuran-2-yl-CH═CH— —CH₂—CH₂— 168 2′-(2-hydroxyethyl)biphen-3-yl—CH₂—CH₂— 169 5-thiophen-3-ylpyridin-3-yl —CH₂—CH₂— 1706-(4-acetylaminophenoxy)pyridin-2-yl —CH₂—CH₂— 1716-(4-aminophenoxy)pyridin-2-yl —CH₂—CH₂— 172 trans2-methoxyphenyl-CH═CH— —CH₂—CH₂— 173 trans 3-methoxyphenyl-CH═CH——CH₂—CH₂— 174 5-(4-dimethylaminophenyl)pyridin-3-yl —CH₂—CH₂— 175 trans5-bromothiophen-2-yl-CH═CH— —CH₂—CH₂— 176 trans furan-3-yl-CH═CH——CH₂—CH₂— 177 trans thiophen-3-yl-CH═CH— —CH₂—CH₂— 178 transthiophen-2-yl-CH═CH— —CH₂—CH₂— 179 trans 3-tolyl-CH═CH— —CH₂—CH₂— 180trans 4-tolyl-CH═CH— —CH₂—CH₂— 181 trans benzofuran-2-yl-C(CH₃)═CH——CH₂—CH₂— 182 cis benzofuran-2-yl-C(CH₃)═CH— —CH₂—CH₂— 183 trans4-dimethylaminophenyl-CH═CH— —CH₂—CH₂— 184 trans indol-3-yl-CH═CH——CH₂—CH₂— 185 trans 2-tolyl-CH═CH— —CH₂—CH₂— 186 trans2-hydroxyphenyl-CH═CH— —CH₂—CH₂— 187 trans7-methoxybenzofuran-2-yl-CH═CH— —CH₂—CH₂— 188 trans7-methoxybenzofuran-2-yl-CH═CH— -(R)-CH(CH₂CH₃)—CH₂— 189 trans5-methoxybenzofuran-2-yl-C(CH₃)═CH— -(S)-CH(CH₂CH₃)—CH₂— 190 transfuran-2-yl-CH═CH— —CH₂—CH₂— 1914-[4-(2-morpholin-4-ylethyl)thiazol-2-yl]phenyl —CH₂—CH₂—and are named as:

-   N-hydroxy-4-(2-benzenecarbonylamino-ethoxy)benzamide;-   N-hydroxy-4-(2-trans-cinnamoylaminoethoxy)benzamide;-   N-hydroxy-4-(2-trans-2-phenylcyclopropylcarbonylaminoethoxy)benzamide;-   N-hydroxy-4-(2-trans-4-methoxycinnamoylaminoethoxy)benzamide;-   N-hydroxy-4-[2-(2-phenylethylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(1H-indol-3-ylmethylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-(2-thiophen-2-ylcarbonylaminoethoxy)benzamide;-   N-hydroxy-4-(2-pyridin-3-ylcarbonylaminoethoxy)benzamide;-   N-hydroxy-4-(2-biphen-4-ylcarbonylaminoethoxy)benzamide;-   N-hydroxy-4-(2-biphen-3-ylcarbonylaminoethoxy)benzamide;-   N-hydroxy-4-[2-(5-phenylthiophen-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(thiophen-2-ylmethylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(napth-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(quinolin-6-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-phenylthiazol-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-tert-butylphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(trans-3-pyridin-3-ylacryloylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-pyrrol-1-ylphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-cyclohexene-3-oxyphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(benzthiazol-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(benzoxazol-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(octahydroisoquinolin-2-ylmethylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-pyridin-4-ylpiperazin-1-ylmethylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(furan-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-pyridin-3-ylphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-pyridin-2-ylphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(benzimidazol-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(1H-pyrrol-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-benzoylaminophenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-pyridin-4-ylthiazol-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(admantan-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(2,4-difluorophenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3-trans-3,4-methylenedioxyphenylacryloylaminonethoxy]-benzamide;-   N-hydroxy-4-[2-(3,4-methylenedioxyphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3,4-dimethoxyphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3,5-dimethoxyphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3,4-difluorophenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(2,5-dimethylphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(2,3-dichlorophenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(2,3-dimethylphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-chloro-2-methoxyphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3-ethoxyphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-methoxy-2-methylphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3-fluoro-4-methoxyphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(2-thiophen-2-ylmethoxyphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3-thiophen-2-ylmethoxyphenylarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(biphen-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(1H-indol-5-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(1H-indol-3-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(quinolin-3-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(quinolin-8-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(1H-indazol-3-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(1H-benzotriazol-5-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(isoquinolin-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(isoquinolin-3-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(quinoxalin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(naphth-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(quinolin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(2-pyrrol-1-ylphenylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-fluoronapth-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(1H-benzimidazol-5-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(1-methylindol-3-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-methoxyquinolin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3-methoxynapth-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(2-methoxynapth-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(quinolin-4-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(trans-2-methylcinnamoylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(2-N,N-dimethylaminomethylbenzofuran-5-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-(2-indolin-1-ylcarbonylaminoethoxy)benzamide;-   N-hydroxy-4-[2-(1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-{2S-[trans-3-(5-hydroxybenzofuran-2-yl)but-2-enoylamino]butoxy}benzamide;-   N-hydroxy-4-{2S-[trans-3-(5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl)but-2-enoyl-amino]butoxy}benzamide;-   N-hydroxy-4-[2S-(benzofuran-2-ylcarbonylamino)-4-phenylbutoxy)benzamide;-   N-hydroxy-4-{2-[5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2S-[5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino]-butoxy}benzamide;-   N-hydroxy-4-{2-[5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino]-1R-methylethoxy}benzamide;-   N-hydroxy-4-{2-[5-(1-(2,2,2-trifluoroethyl)piperidin-4-yloxy)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-[2R-(benzofuran-2-ylcarbonylamino)-3-benzylsulfonylpropoxy]-benzamide;-   N-hydroxy-4-[2R-(benzofuran-2-ylcarbonylamino)-3-benzylthiopropoxy]benzamide;-   N-hydroxy-4-[2-(trans-3-(5-methoxybenzofuran-2-yl)but-2-enoylcarbonylamino)-ethoxy]benzamide;-   N-hydroxy-4-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(isoindolin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(morpholin-4-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-benzylpiperazin-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3(R)-hydroxypyrrolidin-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(piperidin-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(6-methyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(2-methylindolin-1-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)-ethoxy]benzamide;-   N-hydroxy-4-[2S-(isoindolin-1-ylcarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[3-(trans-cinnamoylamino)propoxy]benzamide;-   N-hydroxy-4-[3-(trans-4-methoxycinnamoylamino)propoxy]benzamide;-   N-hydroxy-4-[3-(4-phenylthiazol-2-ylcarbonylamino)propoxy]benzamide;-   N-hydroxy-4-[2S-trans-cinnamoylamino)propoxy)benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)propoxy)benzamide;-   N-hydroxy-4-[2S-trans-cinnamoylamino)-4-methylpentoxy]benzamide;-   N-hydroxy-4-[2S-trans-cinnamoylamino)-3-cyclohexylpropoxy]benzamide;-   N-hydroxy-4-[2S-(trans-cinnamoylamino)-3-methylbutoxy]benzamide;-   N-hydroxy-4-[2S-(trans-cinnamoylamino)-3-phenylpropoxy]benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)-3-phenylpropoxy]benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)-4-methylpentoxy]benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)-3-methylbutoxy]benzamide;-   N-hydroxy-4-[2RS-(trans-cinnamoylamino)hexyloxy]benzamide;-   N-hydroxy-4-[2RS-(trans-cinnamoylamino)-3-(4-chlorophenyl)propoxy)benzamide;-   N-hydroxy-4-[2S-(trans-cinnamoyl amino)butoxy]benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)butoxy]benzamide;-   N-hydroxy-4-[2S-(trans-cinnamoylamino)-4-methylthiobutoxy)benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)-4-methylthiobutoxy]benzamide;-   N-hydroxy-4-[2S-(trans-cinnamoylamino)-2-phenylethoxy]benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)-2-phenylethoxy]benzamide;-   N-hydroxy-4-[2S-(trans-cinnamoylamino)-4-methylsulfonylbutoxy]benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)-4-methylsulfonylbutoxy]benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)-3-benzylsulfonylpropoxy]benzamide;-   N-hydroxy-4-[2S-(thiophen-2-ylcarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[2S-(biphen-4-ylcarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[2S-(naphth-2-ylcarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[2R-(trans-cinnamoylamino)-3-benzylthiopropoxy]benzamide;-   N-hydroxy-4-[2S-(benzenecarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[2S-(benzylcarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[2S-(2-phenylethylcarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[2S-(trans-cinnamoylamino)-3-hydroxypropoxy]benzamide;-   N-hydroxy-4-[2S-(4-phenylthiazol-2-ylcarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[2S-(trans-4-methoxycinnamoylamino)butoxy]benzamide;-   N-hydroxy-4-[2S-(2-N,N-dimethylaminomethylbenzofuran-5-ylcarbonylamino)-butoxy]-benzamide;-   N-hydroxy-4-[2-(trans-cinnamoylamino)-1R-methylethoxy]benzamide;-   N-hydroxy-4-[2-(trans-cinnamoylamino)-1S-methylethoxy)benzamide;-   N-hydroxy-4-[2-(4-phenylthiazol-2-ylcarbonylamino)-1R-methylethoxy]benzamide;-   N-hydroxy-4-[2-(4-phenylthiazol-2-ylcarbonylamino)-1S-methylethoxy]benzamide;-   N-hydroxy-4-[2-(biphen-4-ylcarbonylamino)-1R-methylethoxy]benzamide;-   N-hydroxy-4-[2-(trans-4-methoxycinnamoylamino)-4R-methylethoxy]benzamide;-   N-hydroxy-4-{2-[4-(2-pyridin-2-ylthiazol-5-yl)phenylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-[2-(7-chloro-4-methylbenzofuran-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-{2-[4-(2-(4-methylpiperazin-1-yl)thiazol-5-yl)phenylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[4-(2-pyridin-4-ylaminothiazol-5-yl)phenylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[4-(4-methylpiperazin-1-yl)phenylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[4-(4-hydroxypiperidin-1-yl)phenylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[4-(4-morpholin-4-ylmethylthiazol-5-yl)phenylcarbonylamino]-ethoxy}-benzamide;-   N-hydroxy-4-[2-(7-fluoro-4-methylbenzofuran-2-ylcarbonylaminonethoxy]benzamide;-   N-hydroxy-4-{2-[7-fluoro-4-(2-methoxyethoxymethyl)benzofuran-2-ylcarbonylamino)-ethoxy}benzamide;-   N-hydroxy-4-[2-(4-hydroxyquinolin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(7-fluoro-4-phenoxymethylbenzofuran-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-{2-[4-(2-(4-methylpiperazin-1-ylmethyl)thiazol-5-yl)phenylcarbonyl-amino]-ethoxy}benzamide;-   N-hydroxy-4-[2-(pyridin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(3-hydroxypyridin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(6-hydroxypyridin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-{2-[6-(4-nitrophenoxy)pyridin-2-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[4-(2-methoxyethoxy)quinolin-2-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[4-(2-N,N-dimethylaminoethoxy)quinolin-2-ylcarbonylamino]-ethoxy}-benzamide;-   N-hydroxy-4-[2-(6-bromopyridin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(5-bromopyridin-3-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2S-(4-methoxyquinolin-2-ylcarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[2-(1-methoxynaphth-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(4-methoxyquinolin-2-ylcarbonylamino)-1R-methylethoxy]benzamide;-   N-hydroxy-4-[2-(5-phenylpyridin-3-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(6-benzyloxypyridin-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-{2-[6-(2-methylpropyloxy)pyridin-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[6-(2-phenylethyloxy)pyridin-2-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[4-(3,3,3-trifluoropropyloxy)quinolin-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2S-[4-(3,3,3-trifluoropropyloxy)quinolin-2-ylcarbonylamino]butoxy}-benzamide;-   N-hydroxy-4-{2-[4-(3,3,3-trifluoropropyloxy)quinolin-2-ylcarbonylamino]-1R-methylethoxy}-benzamide;-   N-hydroxy-4-[2-(trans-3-hydroxycinnamoylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(trans-4-hydroxycinnamoylamino)ethoxy]benzamide;-   N-hydroxy-4-{2-[3′-(2-hydroxyethyl)biphen-4-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[3′-(2-hydroxyethyl)biphen-3-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[2′-(2-hydroxyethyl)biphen-4-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-[2-(trans-2-benzofuran-2-ylacryloylamino)ethoxy]benzamide;-   N-hydroxy-4-{2-[2′-(2-hydroxyethyl)biphen-3-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[5-(thiophen-3-yl)pyridin-3-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[6-(4-acetylaminophenoxy)pyridin-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[6-(4-aminophenoxy)pyridin-2-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-[2-(trans-2-methoxycinnamoylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(trans-3-methoxycinnamoylamino)ethoxy]benzamide;-   N-hydroxy-4-{2-[5-(4-dimethylaminophenyl)pyridin-3-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[trans-3-(5-bromothiophen-2-yl)acryloylamino]ethoxy}benzamide;-   N-hydroxy-4-[2-(trans-3-furan-3-ylacryloylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(trans-3-thiophen-3-ylacryloylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(trans-thiophen-2-ylacryloylamino)ethoxy]benzamide;-   N-hydroxy-4-{2-[trans-3-methylcinnamoylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[trans-4-methylcinnamoylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[trans-3-(benzofuran-2-yl)but-2-enoylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[cis-3-(benzofuran-2-yl)but-2-enoylamino]ethoxy}benzamide;-   N-hydroxy-4-[2-(trans-4-dimethylaminocinnamoylamino)ethoxy]benzamide;-   N-hydroxy-4-[2-(trans-3-indol-3-ylacryloylamino)ethoxy]benzamide;-   N-hydroxy-4-(2-[trans-2-methylcinnamoyl amino]ethoxy)benzamide;-   N-hydroxy-4-[2-(trans-2-hydroxycinnamoylamino)ethoxy]benzamide;-   N-hydroxy-4-{2-[trans-3-(7-methoxybenzofuran-2-yl)acryloylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2R-[trans-3-(7-methoxybenzofuran-2-yl)acryloylamino]butoxy}-benzamide;-   N-hydroxy-4-{2S-[trans-3-(5-methoxybenzofuran-2-yl)but-2-enoylamino]butoxy}-benzamide;-   N-hydroxy-4-[2-(trans-3-furan-2-ylacryloylamino)ethoxy]benzamide;    and-   N-hydroxy-4-{2-[4-(4-(2-morpholin-4-ylethyl)thiazol-2-yl)phenylcarbonylamino]-ethoxy}-benzamide.

Compounds of Formula (I) where R¹ is hydrogen, Ar¹ is phenyl and R³, Ar²and Y are as defined in Table II below are:

TABLE II

Cpd # R³ Ar² Y 1 2-HO-ethyl trans phenyl-CH═CH— —CH₂—CH₂— 2 phenyl transphenyl-CH═CH— —CH₂—CH₂— 3 CH₃ trans phenyl-CH═CH— —CH₂—CH₂— 4 i-propylbenzothiophen-2-yl —CH₂—CH₂— 5 i-propyl trans phenyl-CH═CH— —CH₂—CH₂— 6CH₃ trans phenyl-CH═CH— —CH₂—CH₂—CH₂—and are named as:

-   N-hydroxy-4-(2-N-trans-cinnamoyl-N-hydroxyethylaminoethoxy)benzamide;-   N-hydroxy-4-(2-N-trans-cinnamoyl-N-phenylaminoethoxy)benzamide;-   N-hydroxy-4-(2-N-trans-cinnamoyl-N-methylaminoethoxy)benzamide;-   N-hydroxy-4-(2-N-benzothiophen-2-yl-N-isopropylaminoethoxy)benzamide;-   N-hydroxy-4-(2-N-trans-cinnamoyl-N-isopropylaminoethoxy)benzamide;    and-   N-hydroxy-4-(3-N-trans-cinnamoyl-N-methylaminopropoxy)benzamide.

Compounds of Formula (I) where R¹ and R³ are hydrogen, Ar¹ is phenyl,Ar² and Y are as defined in Table III below are:

TABLE III

Cpd # Z R Y 1 S H —CH₂—CH₂— 2 O H —CH₂—CH₂— 3 NH H —CH₂—CH₂— 4 NMe H—CH₂—CH₂— 5 S H —CH₂—CH₂—CH₂— 6 O H —CH₂—CH₂—CH₂— 7 S H-(S)-CH(i-propyl)-CH₂— 8 S H -(S)-CH(ethyl)-CH₂— 9 S H-(S)-CH(methyl)-CH₂— 10 S H -(R)-CH(methyl)-CH₂— 11 O H-(S)-CH(ethyl)-CH₂— 12 S H -(R)-CH₂—CH(CH₃)— 13 S H -(S)-CH₂—CH(CH₃)— 14O H -(R)-CH₂—CH(CH₃)— 15 S 6-methoxy —CH₂—CH₂— 16 S 5-methyl —CH₂—CH₂—17 S 3-chloro —CH₂—CH₂— 18 O 5-methyl —CH₂—CH₂— 19 O 6-methyl —CH₂—CH₂—20 S 4-CF₃ —CH₂—CH₂— 21 S 5-fluoro —CH₂—CH₂— 22 S 5-methoxy —CH₂—CH₂— 23O 5-chloro —CH₂—CH₂— 24 O 7-methoxy —CH₂—CH₂— 25 O 5-methoxy —CH₂—CH₂—26 O 5-(2-methoxyethoxy)- —CH₂—CH₂— 27 O 5-(2-morpholin-4-ylethoxy)-—CH₂—CH₂— 28 O 5-pyridin-3-ylmethoxy —CH₂—CH₂— 29 O 3-methyl —CH₂—CH₂—30 S 3 methyl —CH₂—CH₂— 31 O 5-(2-hydroxyethoxy)- —CH₂—CH₂— 32 O5-(2-N,N-dimethylaminoethoxy)- —CH₂—CH₂— 33 O 6-CH₃OCH₂CH₂O —CH₂—CH₂— 34O 6-(2-morpholin-4-ylethoxy)- —CH₂—CH₂— 35 O 6-pyridin-3ylmethoxy-—CH₂—CH₂— 36 O 3-ethyl —CH₂—CH₂— 37 NH 5-fluoro —CH₂—CH₂— 38 NH5-methoxy —CH₂—CH₂— 39 O 3-CH₃OCH₂ —CH₂—CH₂— 40 O 3-phenoxymethyl—CH₂—CH₂— 41 NH 5,6-dimethoxy —CH₂—CH₂— 42 O 3-morpholino-4-ylmethyl—CH₂—CH₂— 43 O 3-N,N-dimethylaminomethyl —CH₂—CH₂— 44 O3-i-propoxymethyl —CH₂—CH₂— 45 O 7-phenoxymethyl —CH₂—CH₂— 46 O7-CH₃OCH₂ —CH₂—CH₂— 47 O 7-morpholino-4-ylmethyl —CH₂—CH₂— 48 O7-N,N-dimethylaminomethyl —CH₂—CH₂— 49 S 5-methyl —CH₂—CH₂—CH₂— 50 S6-methoxy —CH₂—CH₂—CH₂— 51 O 7-CH₃OCH₂ —CH₂—CH₂—CH₂— 52 O7-phenoxymethyl —CH₂—CH₂—CH₂— 53 O 5-CH₃OCH₂CH₂O -(R)-CH₂—CH(CH₃)— 54 OH (R)-CH(CH₃Smethyl)-CH₂— 55 O H (R)-CH(CH₃SO₂-methyl)-CH₂— 56 O3-(2-phenylethyl)- —CH₂—CH₂— 57 O 3-(N-methyl-N-benzylaminomethyl)-—CH₂—CH₂— 58 O 3-(N-methyl-N-2-phenylethylamino- —CH₂—CH₂— methyl)- 59 O3-(3-hydroxypropylthiomethyl)- —CH₂—CH₂— 60 O3-(3-hydroxypropylsulfinyl-methyl)- —CH₂—CH₂— 61 O3-(3-hydroxypropylsulfonyl-methyl)- —CH₂—CH₂— 62 O3-(N-methyl-N-2-indol-3-yl- —CH₂—CH₂— ethylaminomethyl)- 63 O3-[2-(3-trifluoromethyl-phenyl)ethyl]- —CH₂—CH₂— 64 O3-[2-(3-trifluoromethoxy-phenyl)ethyl]- —CH₂—CH₂— 65 O3-(N-hydroxyaminocarbonyl- —CH₂—CH₂— methylaminomethyl)- 66 O3-(2-carboxyethylamino-methyl)- —CH₂—CH₂— 67 O H(RS)-CH₂CH—(phenoxymethyl)- 68 O 3-(3-hydroxypropyloxy-methyl)-—CH₂—CH₂— 69 O 3-(2-fluorophenoxymethyl)- —CH₂—CH₂— 70 O3-(3-fluorophenoxymethyl)- —CH₂—CH₂— 71 O 3-(4-fluorophenoxymethyl)-—CH₂—CH₂— 72 O 3-(2-methoxyethyloxymethyl)- —CH₂—CH₂— 73 O3-(pyridin-4-yloxymethyl)- —CH₂—CH₂— 74 O3-(2,4,6-trifluorophenoxy-methyl)- —CH₂—CH₂— 75 O3-(2-oxopyridin-1-ylmethyl)- —CH₂—CH₂— 76 O3-(2,2,2-trifluoroethoxy-methyl)- —CH₂—CH₂— 77 O3-(4-imidazol-1-ylphenoxy-methyl)- —CH₂—CH₂— 78 O3-(4-[1.2.4]-triazin-1-yl-phenoxy- —CH₂—CH₂— methyl)- 79 O3-(pyrrolidin-1-ylmethyl)- —CH₂—CH₂— 80 O 3-(piperidin-1-ylmethyl)-—CH₂—CH₂— 81 O 3-(4-trifluoromethylpiperidin-ylmethyl)- —CH₂—CH₂— 82 O3-(4-methylpiperazin-1-yl-methyl)- —CH₂—CH₂— 83 O3-(3,3,3-trifluoropropyloxy-methyl)- —CH₂—CH₂— 84 O 4-methyl —CH₂—CH₂—85 O 3-(4-fluorophenylthiomethyl)- —CH₂—CH₂— 86 O3-(4-fluorophenylsulfinyl-methyl)- —CH₂—CH₂— 87 O3-(4-fluorophenylsulfonyl-methyl)- —CH₂—CH₂— 88 O3-(2,2,2-trifluoroethoxy-methyl)- (S)-CH(ethyl)-CH₂— 89 O 4-hydroxy—CH₂—CH₂— 90 O 5-chloro (S)-CH(ethyl)-CH₂— 91 O 5-chloro(R)-CH₂—CH(methyl)- 92 O 4-pyridin-3-ylmethyloxy-methyl —CH₂—CH₂— 93 O4-methoxy —CH₂—CH₂— 94 O 4-(2-methoxyethyloxy)- —CH₂—CH₂— 95 O4-pyridin-3-ylmethyloxy —CH₂—CH₂— 96 NH 4-methoxy —CH₂—CH₂— 97 O3-(2-methoxyethyloxymethyl)- (S)-CH(ethyl)-CH₂— 98 O3-(2-methoxyethyloxymethyl)- (R)-CH₂—CH(methyl)- 99 O3-N,N-diethylaminomethyl —CH₂—CH₂— 100 O 5-(2-methoxyethyloxy)-(S)-CH(ethyl)-CH₂— 101 O 5-tetrahydropyran-4-yloxy —CH₂—CH₂— 102 O5-tetrahydropyran-4-yloxy (S)-CH(ethyl)-CH₂— 103 O5-tetrahydropyran-4-yloxy (R)-CH₂—CH(methyl)- 104 O5-(2,2,2-trifluoroethyloxy)- —CH₂—CH₂— 105 O5-(2-pyrrolidin-1-ylethyloxy)- —CH₂—CH₂— 106 O5-(2-pyrrolidin-1-ylethyloxy)- (S)-CH(ethyl)-CH₂— 107 O5-(2-pyrrolidin-1-ylethyloxy)- (R)-CH₂—CH(methyl)- 108 O5-(piperidin-4-yloxy)- —CH₂—CH₂— 109 O H (S)-CH(2-CH₃Sethyl)-CH₂— 110 OH (S)-CH(2-CH₃SO₂-ethyl)-CH₂—and are named as:

-   N-hydroxy-4-[2-(benzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(1H-indol-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(1-methylindol-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[3-(benzothiophen-2-ylcarbonylamino)propoxy]-benzamide;-   N-hydroxy-4-[3-(benzofuran-2-ylcarbonylamino)propoxy]-benzamide;-   N-hydroxy-4-[2S-(benzothiophen-2-ylcarbonylamino)-3-methylbutoxy]-benzamide;-   N-hydroxy-4-[2S-(benzothiophen-2-ylcarbonylamino)butoxy]-benzamide;-   N-hydroxy-4-[2S-(benzothiophen-2-ylcarbonylamino)-propoxy]-benzamide;-   N-hydroxy-4-[2R-(benzothiophen-2-ylcarbonylamino)-propoxy]-benzamide;-   N-hydroxy-4-[2S-(benzofuran-2-ylcarbonylamino)butoxy]-benzamide;-   N-hydroxy-4-[2-(benzothiophen-2-ylcarbonylamino)-1R-methylethoxy]-benzamide;-   N-hydroxy-4-[2-(benzothiophen-2-ylcarbonylamino)-1S-methylethoxy]-benzamide;-   N-hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)-1R-methylethoxy]-benzamide;-   N-hydroxy-4-[2-(6-methoxybenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(5-methylbenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide,-   N-hydroxy-4-[2-(3-chlorobenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(5-methylbenzofuran-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(6-methylbenzofuran-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(4-trifluoromethylbenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(5-fluorobenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(5-methoxybenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(5-chlorobenzofuran-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(7-methoxybenzofuran-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(5-methoxybenzofuran-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-{2-[5-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[5-(2-morpholin-4-ylethoxy)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[5-(pyridin-3-ylmethoxy)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-[2-(3-methylbenzofuran-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(3-methylbenzothiophen-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-{2-[5-(2-hydroxyethoxy)benzofuran-2-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[5-(2-N,N-dimethylaminoethoxy)benzofuran-2-ylcarbonylamino]-ethoxy}-benzamide;-   N-hydroxy-4-{2-[6-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[6-(2-morpholin-4-ylethoxy)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[6-(pyridin-3-ylmethoxy)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-[2-(3-ethylbenzofuran-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(5-fluoroindol-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-[2-(5-methoxyindol-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-{2-[3-(methoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(phenoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-[2-(5,6-dimethoxyindol-2-ylcarbonylamino)ethoxy]-benzamide;-   N-hydroxy-4-{2-[3-morpholin-4-ylmethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]-ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(1-propoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[7-(phenoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[7-(methoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[7-(morpholin-4-ylmethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[7-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]-ethoxy}-benzamide;-   N-hydroxy-4-{3-[5-(methyl)benzothiophen-2-ylcarbonylamino]propoxy}-benzamide;-   N-hydroxy-4-{3-[6-(methoxy)benzothiophen-2-ylcarbonylamino]propoxy}-benzamide;-   N-hydroxy-4-{3-[7-(methoxymethyl)benzofuran-2-ylcarbonylamino]propoxy}-benzamide;-   N-hydroxy-4-{3-[7-(phenoxymethyl)benzofuran-2-ylcarbonylamino]propoxy}-benzamide;-   N-hydroxy-4-{2-[5-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino]-1R-methyl    ethoxy}benzamide.-   N-hydroxy-4-(2R-benzofuran-2-ylcarbonylamino-3-methylthiopropoxy)benzamide;-   N-hydroxy-4-(2R-benzofuran-2-ylcarbonylamino-3-methylsulfonylpropoxy)benzamide;-   N-hydroxy-4-{2-[3-(2-phenylethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(N-methyl-N-benzylaminomethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(N-methyl-N-2-phenylethylaminomethyl)benzofuran-2-ylcarbonyl-amino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(3-hydroxypropylthiomethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(3-hydroxypropylsulfinylmethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(3-hydroxypropylsulfonylmethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(N-methyl-N-2-indol-3-ylethylaminomethyl)benzofuran-2-yl-carbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(2-(3-trifluoromethylphenyl)ethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(2-(3-trifluoromethoxyphenyl)ethyl)benzofuran-2-ylcarbonyl-amino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(N-hydroxyaminocarbonylmethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(2-carboxyethylaminomethy)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;    and-   N-hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)-1RS-phenoxymethylethoxy}-benzamide.-   N-hydroxy-4-{2-[3-(3-hydroxypropoxymethyl)benzofuran-2-ylcarbonylamino]-ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(2-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(3-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(4-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino]-ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(pyridin-4-yloxymethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(2,4,6-trifluorophenoxymethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(2-oxopyridin-1-ylmethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(4-imidazol-1-ylphenoxymethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(4-[1.2.4]-triazin-1-ylphenoxymethyl)benzofuran-2-ylcarbonyl-amino]ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(pyrrolidin-1-methyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(piperidin-1-methyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(4-trifluoromethylpiperidin-1-methyl)benzofuran-2-ylcarbonyl-amino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(4-methylpiperazin-1-methyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(3,3,3-trifluoropropyloxymethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-[2-(4-methylbenzofuran-2-ylcarbonylamino)-ethoxy]benzamide;-   N-hydroxy-4-{2-[3-(4-fluorophenylthiomethyl)benzofuran-2-ylcarbonylamino]-ethoxy}-benzamide;-   N-hydroxy-4-{2-[3-(4-fluorophenylsulfinylmethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(4-fluorophenylsulfonylmethyl)benzofuran-2-ylcarbonylamino]-ethoxy}benzamide;-   N-hydroxy-4-{2S-[3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-ylcarbonylamino]-butoxy}benzamide;-   N-hydroxy-4-[2-(4-hydroxybenzofuran-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-[2S-(5-chlorobenzofuran-2-ylcarbonylamino)butoxy]benzamide;-   N-hydroxy-4-[2-(5-chlorobenzofuran-2-ylcarbonylamino]-1R-methylethoxy]-benzamide;-   N-hydroxy-4-[2-(4-pyridin-3-ylmethyloxymethylbenzofuran-2-ylcarbonylamino)-ethoxy]benzamide;-   N-hydroxy-4-[2-(4-methoxybenzofuran-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-{2-[4-(2-methoxyethyloxy)benzofuran-2-ylcarbonylamino)ethoxy}-benzamide;-   N-hydroxy-4-[2-(4-pyridin-3-ylmethyloxybenzofuran-2-ylcarbonylamino)-ethoxy]benzamide;-   N-hydroxy-4-[2-(4-methoxyindol-2-ylcarbonylamino)ethoxy]benzamide;-   N-hydroxy-4-{2S-[3-(2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino]-butoxy}-benzamide;-   N-hydroxy-4-{2-[3-(2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino]-1R-methyl-ethoxy}benzamide;-   N-hydroxy-4-{2-[3-(N,N-diethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2S-[5-(2-methoxyethyloxy)benzofuran-2-ylcarbonylamino]butoxy}-benzamide;-   N-hydroxy-4-{2-[5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-{2S-[5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino]-butoxy}-benzamide;-   N-hydroxy-4-{2-[5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino]-1R-methyl-ethoxy}benzamide;-   N-hydroxy-4-{2-[5-(2,2,2-trifluoroethyloxy)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-(2-[5-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino]-ethoxy)-benzamide;-   N-hydroxy-4-{2S-[5-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino]-butoxy}-benzamide;-   N-hydroxy-4-{2-[5-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino]-1R-methyl-ethoxy}benzamide;-   N-hydroxy-4-{2-[5-(piperidin-4-yloxy)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide;-   N-hydroxy-4-[2S-(benzofuran-2-ylcarbonylamino)-4-methylthiobutoxy]benzamide;    and-   N-hydroxy-4-[2S-(benzofuran-2-ylcarbonylamino)-4-methylsulfonylbutoxy]benzamide.

Compounds of Formula (I) where R¹ and R³ are hydrogen, Ar¹ isisoxazol-5-yl and Ar² and Y are as defined in Table IV below are:

TABLE IV

Cpd # Ar² Y 1 4-biphenyl (R)-CH₂—CH(CH₃)— 2 4-biphenyl(S)-CH(ethyl)-CH₂— 3 benzofuran-2-yl —CH₂—CH₂— 4 trans phenyl-CH═CH——CH₂—CH₂— 5 4-(2-ethoxyphenyl)phenyl —CH₂—CH₂—CH₂— 6 3-biphenyl—CH₂—CH₂—CH₂— 7 4-biphenyl —CH₂—CH₂—CH₂— 8 naphth-2-yl —CH₂—CH₂— 93-methylbiphen-4-yl —CH₂—CH₂— 10 2′-ethoxybiphen-4-yl —CH₂—CH₂— 113-methylbiphen-4-yl —CH₂—CH₂—CH₂— 12 4-phenylthiazol-2-yl —CH₂—CH₂—CH₂—13 naphth-2-yl —CH₂—CH₂—CH₂— 14 naphth-1-yl —CH₂—CH₂—CH₂— 152-(2-phenylethyl)phenyl —CH₂—CH₂—CH₂— 16 naphth-1-yl —CH₂—CH₂— 17benzofuran-2-yl (S)-CH(ethyl)-CH₂— 18 3-biphenyl (S)-CH(ethyl)-CH₂— 19benzofuran-2-yl (R)-CH₂—CH(methyl)- 20 3-biphenyl (R)-CH₂—CH(methyl)- 213-biphenyl —CH₂—CH₂— 22 4-biphenyl —CH₂—CH₂— 23 4-phenylthiazol-2-yl—CH₂—CH₂— 24 2-(2-phenylethyl)phenyl —CH₂—CH₂— 25 2-biphenyl —CH₂—CH₂—26 2-biphenyl —CH₂—CH₂—CH₂— 27 naphth-2-yl (S)-CH(ethyl)-CH₂— 28naphth-1-yl (S)-CH(ethyl)-CH₂— 29 naphth-2-yl (R)-CH₂—CH(methyl)- 30naphth-1-yl (R)-CH₂—CH(methyl)- 31 benzofuran-2-yl —CH₂—CH₂—CH₂— 32trans phenylCH═CH— —CH₂—CH₂—CH₂— 33 3-(phenoxymethyl)benzofuran-2-yl—CH₂—CH₂—are named as:

-   N-hydroxy-3-[2-(biphen-4-ylcarbonylamino)-1R-methylethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2S-(biphen-4-ylcarbonylamino)butoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(benzofuran-2-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(trans-cinnamoylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(4-(2-ethoxyphenyl)phenylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(biphen-3-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(biphen-4-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(naphth-2-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(3-methylbiphen-4-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(2′-ethoxylbiphen-4-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(3-methylbiphen-4-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(4-phenylthiazol-2-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(naphth-2-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(naphth-1-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-{3-[2-(2-phenylethyl)phenylcarbonylamino]propoxy}isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(naphth-1-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2S-(benzofuran-2-ylcarbonylamino)butoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2S-(biphen-3-ylcarbonylamino)butoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(benzofuran-2-ylcarbonylamino)-1R-methylethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(biphen-3-ylcarbonylamino)-1R-methylethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(biphen-3-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(biphen-4-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(4-phenylthiazol-2-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-{2-[2-(2-phenylethyl)phenylcarbonylamino]ethoxy}isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(biphen-2-ylcarbonylamino)ethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(biphen-2-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2S-(naphth-2-ylcarbonylamino)butoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2S-(naphth-1-ylcarbonylamino)butoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(naphth-2-ylcarbonylamino)-1R-methylethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[2-(naphth-1-ylcarbonylamino)-1R-methylethoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(benzofuran-2-ylcarbonylamino)propoxy]isoxazol-5-ylcarboxamide;-   N-hydroxy-3-[3-(trans-cinnamoylamino)propoxy]isoxazol-5-ylcarboxamide;    and-   N-hydroxy-3-[2-(3-phenoxymethylbenzofuran-2-ylcarbonylamino)ethoxy]isoxazol-5-yl-carboxamide.

PREFERRED EMBODIMENTS

While the broadest definition of this invention is set forth in theSummary of the Invention, certain compounds of Formula (I) arepreferred. For example:

1. A preferred group of compounds of Formula (I) is that wherein:

R¹ is hydrogen or alkyl;

X is —O—, —NR²—, or —S(O), where n is 0-2 and R² is hydrogen or alkyl;

Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkysulfonyl, optionally substitutedphenylalkylthio, optionally substituted phenylalkylsulfonyl, or hydroxy;

Ar¹ is phenylene or heteroarylene wherein said Ar¹ is optionallysubstituted with one or two groups independently selected from alkyl,halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;

R³ is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl;and

Ar² is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl;

wherein the terms aryl, heteroaryl, heterocycloalkyl, optionallysubstituted phenyl, optionally substituted heteroaryl, optionallysubstituted heterocycloalkyl, and aminoalkyl either alone or as part ofanother term (e.g., aralkyl, optionally substituted phenylalkylthio,aminoalkoxy, optionally substituted phenylcarbonylamino, optionallysubstituted heteroaryl, etc) contained within the scope of preferredGroup I above, have the meaning given below:

“aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 12 ring atoms e.g., phenyl, naphthyl or anthracenyloptionally substituted with one, two, or three substituentsindependently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy,amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy,hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionally substituted phenyl,optionally substituted heteroaryl, cycloalkyloxy, cycloalkenyloxy,optionally substituted phenylcarbonylamino, optionally substitutedheteroaryloxy, optionally substituted heteroaralkyloxy, aminoalkyl,aminoalkoxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy,haloalkoxyalkyl, optionally substituted phenyloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substitutedheterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl,optionally substituted heterocycloalkylalkyloxy, optionally substitutedheterocycloalkyloxy, -alkylene-S(O)_(n)—R^(a) (where n is 0 to 2 andR^(a) is alkyl, haloalkyl, optionally substituted phenyl, optionallysubstituted phenylalkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl), -alkylene-NHSO₂—R^(b) (whereR^(b) is alkyl, haloalkyl, optionally substituted phenyl, optionallysubstituted phenylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, or optionally substituted heterocycloalkyl),or -alkylene-NHCO—R^(c) (where R^(c) is alkyl, haloalkyl, optionallysubstituted phenyl, optionally substituted phenylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyl, oroptionally substituted heterocycloalkyl) wherein the alkyl chain inhaloalkoxyalkyl, optionally substituted phenyloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or aminoalkyl is optionally substitutedwith one or two fluoro. More preferably, the aryl ring is optionallysubstituted with one, two, or three substituents independently selectedfrom alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino,dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, optionallysubstituted phenyl, optionally substituted phenylalkyl, optionallysubstituted heteroaryl, cycloalkyloxy, cycloalkenyloxy, optionallysubstituted phenylcarbonylamino, optionally substituted heteroaryl,optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkoxy,alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, optionally substitutedphenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted heterocycloalkylalkyl, optionally substitutedheterocycloalkylalkyloxy, optionally substitutedheterocycloalkyloxyalkyl, or optionally substituted heterocycloalkyloxy.Preferably, the substituents are independently methoxy, methyl, ethyl,chloro, trifluoromethyl, fluoro, 2-methoxyethoxy,2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy,2-(N,N-dimethylamino)ethoxy, methoxymethyl, phenoxymethyl,2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N,N-dimethylaminomethyl,i-propoxymethyl, or phenoxymethyl;

“heterocycloalkyl” means a saturated monovalent cyclic group of 3 to 8ring atoms in which one or two ring atoms are heteroatoms selected fromN, O, or S(O)_(n), where n is an integer from 0 to 2, the remaining ringatoms being C. More specifically the term heterocycloalkyl includes, butis not limited to, pyrrolidino, piperidino, morpholino, piperazino,tetrahydropyranyl, and thiomorpholino, and the derivatives thereof(formed when the heterocycloalkyl ring is substituted with a substituentlisted below); or an N-oxide or a protected derivative thereof. Theheterocycloalkyl is optionally fused to aryl and is optionallysubstituted with one, two, or three substituents independently selectedfrom alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, amino,alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkyloxy, optionallysubstituted phenyl, optionally substituted heteroaryl, cycloalkyloxy,cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionallysubstituted heteroaryl, optionally substituted heteroaralkyloxy,aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy,optionally substituted phenyloxyalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy,or optionally substituted heterocycloalkyloxy. Preferably, thesubstituents are independently methoxy, methyl, ethyl, chloro,trifluoromethyl, fluoro, 2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy,pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-(N,N-dimethylamino)ethoxy,methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl,morpholino-4-ylmethyl, N,N-dimethylaminomethyl, i-propoxymethyl, orphenoxymethyl;

“heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms containing one or more, preferably one, two, orthree ring heteroatoms selected from N, O, or S, the remaining ringatoms being carbon. More specifically the term heteroaryl includes, butis not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl,indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,isoxazolyl, benzoxazolyl, benzothiophenyl, benzthiazolyl, quinolinyl,isoquinolinyl, benzopyranyl, and thiazolyl, and the derivatives thereof(formed when the heteroaryl ring is substituted with a substituentlisted below), or an N-oxide or a protected derivative thereof. Theheteroaryl ring is optionally substituted with one, two, or threesubstituents independently selected from alkyl, alkoxy, halo, haloalkyl,haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl,hydroxyalkyloxy, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionallysubstituted phenyl, optionally substituted heteroaryl, cycloalkyloxy,cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionallysubstituted heteroaryl, optionally substituted heteroaralkyloxy,aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy,haloalkoxyalkyl, optionally substituted phenyloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substitutedheterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl,optionally substituted heterocycloalkylalkyloxy, optionally substitutedheterocycloalkyloxy, -alkylene-S(O)_(n)—R^(a) (where n is 0 to 2 andR^(a) is alkyl, haloalkyl, optionally substituted phenyl, optionallysubstituted phenylalkyl, optionally substituted heteroaryl, oroptionally substituted heteroaralkyl), -alkylene-NHSO₂—R^(b) (whereR^(b) is alkyl, haloalkyl, optionally substituted phenyl, optionallysubstituted phenylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroaralkyl, or optionally substituted heterocycloalkyl),or -alkylene-NHCO—R^(c) (where R^(c) is alkyl, haloalkyl, optionallysubstituted phenyl, optionally substituted phenylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyl, oroptionally substituted heterocycloalkyl) wherein the alkyl chain inhaloalkoxyalkyl, optionally substituted phenyloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or aminoalkyl is optionally substitutedwith one or two fluoro. More preferably, the substituents areindependently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy,amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy,optionally substituted phenyl, optionally substituted heteroaryl,cycloalkyloxy, cycloalkenyloxy, optionally substitutedphenylcarbonylamino, optionally substituted heteroaryl, optionallysubstituted heteroaralkyloxy, aminoalkyl, aminoalkoxy, alkoxyalkyl,alkoxyalkyloxy, methylenedioxy, optionally substituted phenyloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedheterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl,optionally substituted heterocycloalkylalkyloxy, or optionallysubstituted heterocycloalkyloxy. Preferably, the substituents areindependently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro,2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy,2-hydroxyethoxy, 2-(N,N-dimethylamino)ethoxy, methoxymethyl,phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl,N,N-dimethylaminomethyl, i-propoxymethyl, or phenoxymethyl;

“optionally substituted phenyl” means a phenyl ring optionallysubstituted with one, two, or three substituents independently selectedfrom alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, heteroaryl(that is optionally substituted with one or two substituentsindependently selected from alkyl, halo, hydroxy, alkoxy, carboxy,amino, alkylamino, or dialkylamino), heterocycloalkyl (that isoptionally substituted with one or two substituents independentlyselected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino,or dialkylamino), amino, alkylamino, dialkylamino, hydroxy, cyano,nitro, methylenedioxy, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl,aminoalkyl, or carboxy or optionally substituted with five fluorineatoms. More preferably, the substituents are independently selected fromalkyl, halo, alkoxy, alkylthio, trifluoromethyl, trifluoromethoxy,amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy,aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy oroptionally substituted with five fluorine atoms;

-   “optionally substituted heteroaryl” means a monovalent monocyclic or    bicyclic aromatic radical of 5 to 10 ring atoms containing one or    more, preferably one, two, or three ring heteroatoms selected from    N, O, or S, the remaining ring atoms being carbon which is    optionally substituted with one, two, or three substituents    independently selected from alkyl, halo, alkoxy, trifluoromethyl,    trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano,    nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl,    optionally substituted phenyl, optionally substituted phenoxy,    carboxy, or heteroaryl that is optionally substituted with alkyl,    halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino.    More specifically the term optionally substituted heteroaryl    includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl,    thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl,    pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl,    isoquinolinyl, benzopyranyl, and thiazolyl, and the derivatives    thereof (formed when the heteroaryl ring is substituted with a    substituent listed below), or an N-oxide or a protected derivative    thereof;

“optionally substituted heterocycloalkyl” a saturated monovalent cyclicgroup of 3 to 8 ring atoms in which one or two ring atoms areheteroatoms selected from N, O, or S(O)_(n), where n is an integer from0 to 2, the remaining ring atoms being C. The heterocycloalkyl isoptionally fused to aryl and is optionally substituted with one, two, orthree substituents independently selected from alkyl, halo, alkoxy,trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino,hydroxy, cyano, nitro, optionally substituted phenylalkyl, optionallysubstituted heteroaralkyl, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl,aminoalkyl, or carboxy. More specifically the term heterocycloalkylincludes, but is not limited to, pyrrolidino, piperidino, morpholino,piperazino, tetrahydropyranyl, and thiomorpholino, and the derivativesthereof (formed when the heterocycloalkyl ring is substituted with asubstituent listed below); or an N-oxide or a protected derivativethereof; and

“aminoalkyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with at least one, preferably one or two, —NRR′where R and R′ are independently selected from hydrogen, alkyl, or—COR^(a) where R^(a) is alkyl, or an N-oxide derivative, or a protectedderivative e.g., aminomethyl, methylaminoethyl,2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl,diethylaminoethyl, acetylaminopropyl, and the like; and

the other terms contained within the scope of preferred Group I are asdefined in the definition section of this Application.

Within this group I:

(A). A preferred group of compounds is that wherein R¹ and R³ arehydrogen, X is —O— and Y is ethylene or n-propylene, preferablyethylene.

(B). Another preferred group of compounds is that wherein R¹ and R³ arehydrogen, X is —O— and Y is —CH(C₂H₅)CH₂—, —CH(i-C₃H₇)CH₂—, orCH(CH₃)CH₂— and the stereochemistry at the chiral carbon is (S). Morepreferably, Y is —CH(C₂H₅)CH₂—.

(C). Yet another preferred group of compounds is that wherein R¹ and R³are hydrogen, X is —O— and Y is —CH₂CH(CH₃)— and the stereochemistry atthe chiral carbon is (R).

(i) Within the groups (A)-(C), a more preferred group of compounds isthat wherein Ar¹ is phenylene in which the hydroxamate and the X groupare para to each other and Ar² is aryl. Preferably Ar² is phenyl and isoptionally substituted with one or two substituents independentlyselected from methoxy, ethoxy, phenyl, methyl, tert-butyl, pyrrol-1-yl,cyclohexene-3-oxy, pyridin-3-yl, pyridin-2-yl, benzoylamino, fluoro,chloro, or thiophen-2-ylmethoxy. More preferably, Ar² is phenyl,4-biphenyl, 3-biphenyl, 4-tert-butylphenyl, 4-pyrrol-1-ylphenyl,4-(cyclohexene-3-oxy)phenyl, 4-(pyridin-2-yl)phenyl,4-(pyridin-3-yl)-phenyl, 2,4-difluorophenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl, 3,4-difluorophenyl, 2,5-dimethylphenyl,2,3-dichlorophenyl, 2,3-dimethylphenyl, 4-chloro-2-methoxyphenyl,3-ethoxyphenyl, 4-methoxy-2-methylphenyl, 3-fluoro-4-methoxyphenyl,2-thiophen-2-ylmethoxyphenyl, 3-thiophen-2-ylmethoxyphenyl, 2-biphenyl,or 2-pyrrol-1-ylphenyl.

(ii) Within the groups (A)-(C), another more preferred group ofcompounds is that wherein Ar¹ is phenylene in which the hydroxamate andthe X group are para to each other and Ar² is trans aryl-CH═CH—.Preferably Ar² is trans phenyl-CH═CH— and is optionally substituted withalkoxy, preferably methoxy. Preferably, Ar² is trans phenyl-CH═CH—.

(iii) Within the groups (A)-(C), another more preferred group ofcompounds is that wherein Ar¹ is phenylene in which the hydroxamate andthe X group are para to each other and Ar² is heteroaryl-CH═CH—.Preferably Ar² is pyridinyl-CH═CH—. Preferably, Ar² is trans5-bromothiophen-2-yl-CH═CH— or trans indol-3-yl-CH═CH—.

(iv) Within the groups (A)-(C), another more preferred group ofcompounds is that wherein Ar¹ is phenylene in which the hydroxamate andthe X group are para to each other and Ar² is heteroaryl. Preferably Ar²is pyridin-3-yl, thiophen-2-yl, quinolin-6-yl, thiazol-2-yl,benzthiazol-2-yl, benzoxazol-2-yl, furanyl, pyrrol-2-yl, indol-5-yl,indol-3-yl, indazol-3-yl, quinolin-3-yl, quinolin-1-yl, quinolin-8-yl,benzotriazol-4-yl, benzofuran-5-yl, isoquinolin-1-yl, isoquinolin-3-yl,quinoxalin-2-yl, quinolin-2-yl, or benzimidazol-5-yl wherein said ringsare optionally substituted with phenyl, pyridin-4-yl, methyl, methoxy,or dimethylaminomethyl.

(v) Within the groups (A)-(C), another more preferred group of compoundsis that wherein Ar¹ is phenylene in which the hydroxamate and the Xgroup are para to each other and Ar² is indol-2-yl, benzofuran-2-yl orbenzothiophen-2-yl which are optionally substituted with alkyl, alkoxy,halo, haloalkyl, alkoxyalkyloxy, optionally substitutedheterocycloalkylalkyloxy, optionally substituted heteroaralkyloxy,hydroxyalkoxy, aminoalkyl, aminoalkyloxy, alkoxyalkyloxy, alkoxyalkyl,optionally substituted phenyloxyalkyl, or optionally substitutedheterocycloalkylalkyl. Preferably, Ar² is benzofuran-2-yl orbenzothiophen-2-yl wherein benzofuran-2-yl or benzothiophen-2-Y1 isoptionally substituted with methoxy, methyl, chloro, trifluoromethyl,fluoro, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy,2-hydroxyethoxy, 2-N,N-dimethylaminoethoxy, ethyl, methoxymethyl,2-propyloxymethyl, phenoxymethyl, morpholin-4-ylmethyl, orN,N-dimethylaminomethyl which is located at the 3-position or5-position, preferably 3-position of the benzothiophen-2-yl orbenzofuran-2-yl ring. Even more preferably, Ar² is benzofuran-2-yl,3-N,N-dimethylaminomethylbenzofuran-2-yl, or3-phenoxymethylbenzofuran-2-yl.

(vi) Within the groups (A)-(C), another more preferred group ofcompounds is that wherein Ar¹ is phenylene in which the hydroxamate andthe X group are para to each other and Ar² is indol-2-yl,benzofuran-2-yl or benzothiophen-2-yl and is substituted withphenyloxyalkyl, substituted heteroaryloxyalkyl, substitutedheterocycloalkyloxyalkyl, or haloalkoxyalkyl which are located at the3-position of the benzothiophen-2-yl and benzofuran-2-yl rings. Evenmore preferably, Ar² is3-(2,2,2-trifluoroethyloxymethyl)benzofuran-2-yl.

(vii) Within the groups (A)-(C), another more preferred group ofcompounds is that wherein Ar¹ is heteroarylene and Ar² is aryl.Preferably Ar¹ is five membered heteroarylene ring containing one, two,or three heteroatoms independently selected from N, O or S, morepreferably Ar¹ is isoxazolyl where the hydroxamate and the X groups arelocated at the 5- and 3-position of the isoxazolyl ring, the oxygen atomin the ring being position 1 and Ar² is aryl. Preferably Ar² is phenylthat is optionally substituted with one or two substituentsindependently selected from methoxy, ethoxy, phenyl optionallysubstituted with ethoxy or methyl, methyl, tert-butyl, pyrrol-1-yl,cyclohexene-3-oxy, pyridin-3-yl, pyridin-2-yl, benzoylamino, fluoro,chloro, or thiophen-2-ylmethoxy. More preferably, Ar² is phenyl,4-biphenyl, 3-biphenyl, 2-(2-ethoxyphenyl)phenyl, 3-methylbiphen-4-yl,4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4-(cyclohexene-3-oxy)phenyl,4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)-phenyl, 2,4-difluorophenyl,3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-difluorophenyl,2,5-dimethylphenyl, 2,3-dichlorophenyl, 2,3-dimethylphenyl,4-chloro-2-methoxyphenyl, 3-ethoxyphenyl, 4-methoxy-2-methylphenyl,3-fluoro-4-methoxyphenyl, 2-thiophen-2-ylmethoxyphenyl,3-thiophen-2-ylmethoxyphenyl, 2-biphenyl, or 2-pyrrol-1-ylphenyl.

(viii) Within the groups (A)-(C), another more preferred group ofcompounds is that wherein Ar¹ is heteroarylene and Ar² is aryl-CH═CH—.Preferably Ar¹ is five membered heteroarylene ring containing one, two,or three heteroatoms independently selected from N, O or S, morepreferably Ar¹ is isoxazolyl where the hydroxamate and the X groups arelocated at the 5- and 3-position of the isoxazolyl ring, the oxygen atomin the ring being position 1 and Ar² is phenyl-CH═CH— and is optionallysubstituted with alkoxy.

(ix) Within the groups (A)-(C), another more preferred group ofcompounds is that wherein Ar¹ is heteroarylene and Ar² isheteroaryl-CH═CH—. Preferably Ar¹ is five membered heteroarylene ringcontaining one, two, or three heteroatoms independently selected from N,O or S, more preferably Ar¹ is isoxazolyl where the hydroxamate and theX groups are located at the 5- and 3-position of the isoxazolyl ring,the oxygen atom in the ring being position 1 and Ar² is pyridinylCH═CH—.

(x) Within the groups (A)-(C), another more preferred group of compoundsis that wherein Ar¹ is heteroarylene and Ar² is heteroaryl. PreferablyAr¹ is five membered heteroarylene ring containing one, two, or threeheteroatoms independently selected from N, O or S, more preferably Ar¹is isoxazolyl where the hydroxamate and the X groups are located at the5- and 3-position of the isoxazolyl ring, the oxygen atom in the ringbeing position 1 and Ar² is pyridin-3-yl, thiophen-2-yl, quinolin-6-yl,thiazol-2-yl, benzthiazol-2-yl, benzoxazol-2-yl, furanyl, pyrrol-2-yl,indol-5-yl, indol-3-yl, indazol-3-yl, quinolin-3-yl, quinolin-8-yl,benzotriazol-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl,quinolin-2-yl, or benzimidazol-5-yl wherein said rings are optionallysubstituted with phenyl, pyridin-4-yl, methyl, methoxy, ordimethylaminomethyl.

(xi) Within the groups (A)-(C), another more preferred group ofcompounds is that wherein Ar¹ is heteroarylene and Ar² is indol-2-yl,benzofuran-2-yl or benzothiophen-2-yl which are optionally substitutedwith alkyl, alkoxy, halo, haloalkyl, alkoxyalkyloxy, optionallysubstituted heterocycloalkylalkyloxy, optionally substitutedheteroaralkyloxy, hydroxyalkoxy, aminoalkyloxy, alkoxyalkyloxy,alkoxyalkyl, optionally substituted phenyloxyalkyl, or optionallysubstituted heterocycloalkylalkyl. Preferably Ar¹ is a five memberedheteroarylene ring containing one, two, or three heteroatomsindependently selected from N, O or S, more preferably Ar¹ is isoxazolylwhere the hydroxamate and the X groups are located at the 5- and3-position of the isoxazolyl ring, the oxygen atom in the ring beingposition 1 and Ar² is benzofuran-2-yl and benzothiophen-2-yl which areoptionally substituted with methoxy, methyl, chloro, trifluoromethyl,fluoro, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy,2-hydroxyethoxy, 2-N,N-dimethylaminoethoxy, ethyl, methoxymethyl,phenoxymethyl, morpholin-4-ylmethyl, or dimethylaminomethyl and arelocated at the 3-position of the benzothiophen-2-yl and benzofuran-2-ylrings. Even more preferably, Ar² is benzofuran-2-yl or3-phenoxymethylbenzofuran-2-yl.

(xii) Within the groups (A) and (B), another more preferred group ofcompounds is that wherein Ar² is substituted with alkoxyalkyloxy,optionally substituted heterocycloalkylalkyloxy, hydroxyalkoxy,aminoalkyloxy, alkoxyalkyloxy, alkoxyalkyl, optionally substitutedphenyloxyalkyl, optionally substituted heteroaryloxyalkyl, or optionallysubstituted heterocycloalkylalkyl. Within this group, a more preferredgroup of compounds is that wherein Ar¹ and Ar² are as described inpreferred embodiments above.

II. Another preferred group of compounds of Formula (I) is that whereinX is —O—, R¹ is hydrogen, Ar¹ is phenylene and Ar² is heteroaryl; wherethe scope of the terms contained within preferred Group II are asdefined in the definition section of the Application.

Preferably, the compound is represented by Formula (Ia):

wherein:

Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkysulfonyl, optionally substitutedphenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, oroptionally substituted phenoxy; and

Ar² is heteroaryl.

Preferably, Ar² is heteroaryl optionally substituted with one or twosubstituent(s) independently selected from alkyl, halo, haloalkyl,alkoxy, alkoxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkyloxy,alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy,haloalkoxyalkyl, optionally substituted phenyl, optionally substitutedphenoxy, optionally substituted phenylalkyloxy, optionally substitutedphenylalkyl, optionally substituted phenyloxyalkyl, optionallysubstituted heteroaryl, optionally substituted heteroaralkyloxy,optionally substituted heteroaryloxyalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heterocycloalkyloxy,optionally substituted heterocycloalkylalkyloxy, -alkylene-S(O)_(n)R^(a)(where n is 0 to 2 and R^(a) is hydroxyalkyl or optionally substitutedphenyl), -alkylene-NR^(c)-alkyleneCONR^(c)R^(d) (where R^(c) is hydroxyland R^(d) and R^(e) are independently hydrogen or alkyl), orcarboxyalkylaminoalkyl.

Preferably, Ar² is thiophen-2-yl, pyridin-3-yl, quinolin-6-yl,benzothiazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl, benzofuran-5-yl,benzothien-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl,thiazol-2-yl, 1H-indol-2-yl, 1H-indol-5-yl, 1H-indol-3-yl,quinolin-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzotriazol-5-yl,isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl,1H-benzimidazol-5-yl, quinolin-1-yl, pyridin-2-yl, pyridine-2-yl,quinolin-2-yl, furan-3-yl, thiophen-2-yl, or thiophen-3-yl, morepreferably benzofuran-2-yl, or benzothien-2-yl that is optionallysubstituted with one or two substituents described in the paragraphimmediately above.

Even more preferably Ar² is benzofuran-2-yl and is mono-substituted atthe 3-, 4- or 5-position or disubstituted at the 4 and 7 positions,preferably the benzofuran-2-yl is monosubstituted at the 3 or 5 positionwith a substituent described in the paragraph immediately above. Morepreferably, the substituents are independently selected from chloro,fluoro, trifluoromethyl, methyl, ethyl, methoxy,1-cyclopropylpiperidin-4-yloxy,1-(2,2,2-trifluoroethyl)piperidin-4-yloxy, N,N-dimethylaminomethyl,N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl,2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-yl-methoxy,2-hydroxyethoxy, 2-N,N-dimethylaminoethoxy, methoxymethyl,3-i-propoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropyloxymethyl,2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl,3-methoxypropyloxymethyl, pyridin-4-yloxymethyl,2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl,2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl,4-[1.2.4]-triazin-1-yl-phenoxymethyl, 2-phenylethyl,pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl,4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl,pyridin-3-ylmethyloxymethyl, tetrahydropyran-4-yloxy,2,2,2-trifluoroethyloxy, 2-pyrrolidin-1-ylethyloxy, piperidin-4-yloxy,N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl,3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl,3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl,2-(4-trifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl,N-hydroxyaminocarbonyl-methylaminomethyl, or3-(2-carboxyethylaminomethyl.

Even more preferably, Ar² is benzofuran-2-yl that is substituted at the3-position with N,N-dimethylaminomethyl, N,N-diethylaminomethyl,2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxymethyl,pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl,2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxy-methyl,4-imidazol-1-ylphenoxymethyl, 4-[1.2.4]-triazin-1-yl-phenoxymethyl,2-phenylethyl, 3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl,pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl,4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl,2-(3-trifluoromethoxyphenylethyl)-, N-methyl-N-benzylaminomethyl,N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl,3-hydroxypropylsulfinyl-methyl, 3-hydroxypropylsulfonylmethyl,N-methyl-N-2-indol-3-ylethylaminomethyl,2-(4-trifluoromethylphenyl)ethyl,N-hydroxyaminocarbonyl-methylaminomethyl, or 2-carboxyethylamino-methyl.

Even more preferably, Ar² is benzofuran-2-yl that is substituted at the5-position with 1-cyclopropylpiperidin-4-yloxy, piperidin-4-yloxy,tetrahydropyran-4-yloxy, 2,2,2-trifluoroethoxy,2-pyrrolidin-1-ylethyloxy, or 1-(2,2,2-trifluoroethyl)piperidin-4-yloxy.

Even more preferably, Ar² is 7-chloro-4-methylbenzofuran-2-yl,4-methylbenzofuran-2-yl, 7-fluoro-4-methylbenzofuran-2-yl, or7-fluoro-4-phenoxymethylbenzofuran-2-yl.

Even more preferably, Ar² is thiophen-2-yl, pyridin-3-yl,5-phenylthiophen-2-yl, quinolin-6-yl, 4-phenylthiazol-2-yl,benzothiazol-2-yl, benzoxazol-2-yl, furan-2-yl, 1H-benzimidazol-2-yl,1H-pyrrol-2-yl, 4-(pyridin-4-yl)-thiazol-2-yl, 1H-indol-5-yl,1H-indol-3-yl, quinolin-3-yl, quinolin-8-yl, 1H-indazol-3-yl,1H-benzotriazol-5-yl, isoquinolin-1-yl, isoquinolin-3-yl,quinoxalin-2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl,1-methyl-indol-3-yl, 4-MeO-quinolin-2-yl, quinolin-4-yl,4-hydroxyquinolin-2-yl, pyridin-2-yl, 3-hydroxypyridin-2-yl,6-hydroxypyridin-2-yl, 6-(4-nitrophenoxy)pyridin-2-yl,4-(2-methoxyethoxy)quinolin-2-yl,4-(2-dimethylaminoethoxy)quinolin-2-yl, 6-bromopyridin-2-yl,5-bromopyridin-3-yl, 4-methoxyquinolin-2-yl, 5-phenylpyridin-3-yl,6-benzyloxypyridin-2-yl, 6-(2-methylpropyloxy)-pyridin-2-yl,6-(2-phenylethyloxy)pyridin-2-yl,4-(3,3,3-trifluoropropyloxy)quinolin-2-yl, 5-thiophen-3-ylpyridin-3-yl,6-(4-acetylaminophenoxy)-pyridin-2-yl, 6-(4-aminophenoxy)-pyridin-2-yl,or 5-(4-dimethylaminophenyl)pyridin-3-yl.

Within the preferred and more preferred embodiments in group (II):

(D) A more preferred group of compounds is that wherein Y is straightalkylene, preferably ethylene or n-propylene, preferably ethylene.

(E) Another more preferred group of compounds is that wherein Y isbranched alkylene, preferably —CH(C₂H₅)CH₂—, —CH(i-C₃H₇)CH₂—, or—CH(CH₃)CH₂— and the stereochemistry at the chiral carbon is (S). Morepreferably, Y is —H(C₂H₅)CH₂—.

(F) Yet another more preferred group of compounds is that wherein Y is—CH₂CH(CH₃)— and the stereochemistry at the chiral carbon is (R).

(G) Yet another more preferred group of compounds is that wherein Y is—CH(CHR′)CH₂— where R′ is alkylthio, alkysulfonyl, optionallysubstituted phenylalkylthio, optionally substituted phenylalkylsulfonyl,hydroxy, or optionally substituted phenoxy.

III. Another preferred group of compounds of Formula (I) is that whereinX is —O—, R¹ is hydrogen, Ar¹ is phenylene and Ar² is aralkenyl; wherethe scope of the terms contained within preferred Group III are asdefined in the definition section of the Application.

Preferably, the compound is represented by Formula (Ib):

wherein:

Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkysulfonyl, optionally substitutedphenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, oroptionally substituted phenoxy; and

Ar² is aryl(C₂₋₃)alkenyl.

Preferably Ar² represented by the formulae:

where phenyl is optionally substituted with one or two substituentsindependently selected from alkyl, alkoxy, methylenedioxy, dialkylamino,or hydroxy.

Preferably, Ar² is trans phenyl-CH═CH—, trans 4-MeO-phenyl-CH═CH—, trans3,4-methylenedioxyphenyl CH═CH—, trans 3-hydroxyphenyl-CH═CH—, trans4-hydroxyphenyl-CH═CH—, trans 2-methoxyphenyl-CH═CH—, trans3-methoxyphenyl-CH═CH—, trans 3-tolyl-CH═CH—, trans 4-tolyl-CH═CH—,trans 4-dimethylaminophenyl-CH═CH—, trans 2-tolyl-CH═CH—, or trans2-hydroxyphenyl-CH═CH—.

Within this group of compounds, more preferred groups are where Y is asdescribed in (II) D-G above.

IV. Another preferred group of compounds of Formula (I) is representedby Formula (Ic):

wherein:

Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkysulfonyl, optionally substitutedphenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, oroptionally substituted phenoxy; and

Ar² is heteroaryl(C₂₋₃)alkenyl; where the scope of the terms containedwithin preferred Group IV are as defined in the definition section ofthe Application.

Preferably, Ar² is trans heteroaryl-CH═CH— or transheteroaryl-C(CH₃)═CH—, preferably heteroaryl ring is pyridinyl,benzofuranyl, thienyl (thiophene), furanyl, or indolyl optionallysubstituted with one or two substituents selected from hydroxyl, alkoxy,halo, or optionally substituted heterocycloalkoxy.

Preferably, Ar² is trans pyridin-3-yl-CH═CH—, trans5-hydroxybenzofuran-2-yl —C(CH₃)═CH—, trans5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl-C(CH₃)═CH—, trans5-methoxybenzofuran-2-yl-C(CH₃)═CH—, trans benzofuran-2-yl-CH═CH—, trans5-bromothiophen-2-yl-CH═CH—, trans furan-3-yl-CH═CH—, transthiophen-3-yl-CH═CH—, trans thiophen-2-yl-CH═CH—, transbenzofuran-2-yl-C(CH₃)═CH—, cis benzofuran-2-yl-C(CH₃)═CH—, transindol-3-yl CH═CH—, trans 7-methoxybenzofuran-2-yl-CH═CH—, trans5-methoxybenzofuran-2-yl-C(CH₃)═CH—, or trans furan-2-yl-CH═CH.

Within this group of compounds, more preferred groups are where Y is asdescribed in (II) D-G above.

V. Another preferred group of compounds of Formula (I) is that wherein Xis —O—, R¹ is hydrogen, Ar¹ is phenylene and Ar² is aryl; where thescope of the terms contained within preferred Group V are as defined inthe definition section of the Application.

Preferably, the compound is represented by Formula (Id):

wherein:

Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkysulfonyl, optionally substitutedphenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, oroptionally substituted phenoxy; and

Ar² is aryl.

Preferably, the substituents on the aryl ring are independently selectedfrom optionally substituted phenyl, alkyl, alkoxy, halo, optionallysubstituted heteroaryl, optionally substituted cycloalkenyloxy,optionally substituted heteroaralkyloxy, optionally substitutedheterocycloalkyl, optionally substituted phenylcarbonylamino, ormethylenedioxy. More preferably, Ar² is phenyl, 4-biphenyl, 3-biphenyl,4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4-(pyridin-3-yl)phenyl,4-(pyridin-2-yl)phenyl, 4-benzoylamino)phenyl, 2,4-difluorophenyl,3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl,3,4-difluorophenyl, 2,5-dimethylphenyl, 2,3-dichlorophenyl,2,3-dimethylphenyl, 4-chloro-2-methoxyphenyl, 3-ethoxyphenyl,4-methoxy-2-methylphenyl, 3-fluoro-4-methoxyphenyl,2-(thiophen-2-ylmethoxy)phenyl, 3-(thiophen-2-ylmethoxy)-phenyl,2-biphenyl, naphth-1-yl, 2-pyrrol-1-yl-phenyl, 4-fluoronaphth-1-yl,3-MeO-naphth-2-yl, 2-MeO-naphth-1-yl, naphth-2-yl,4-(2-pyridin-4-ylthiazol-5-yl)phenyl,4-[2-(4-methylpiperazin-1-yl)thiazol-5-yl]-phenyl,4-(2-pyridin-4-ylaminothiazol-5-yl)phenyl,4-(4-methylpiperazin-1-yl)phenyl, 4-(4-hydroxypiperidin-1-yl)phenyl,4-(4-morpholin-4-ylmethylthiazol-2-yl)phenyl,4-[2-(4-methylpiperazin-1-ylmethyl)thiazol-5-yl]phenyl,1-methoxynaphth-2-yl, 3′-(2-hydroxyethyl)biphen-4-yl,3′-(2-hydroxyethyl)biphen-3-yl, 2′-(2-hydroxyethyl)biphen-4-yl,2′-(2-hydroxyethyl)biphen-3-yl or4-[4-(2-morpholin-4-yl-ethyl)thiazol-2-yl]phenyl.

Within this group of compounds, more preferred groups are where Y is asdescribed in (II) D-G above.

Reference to the preferred embodiments set forth above is meant toinclude all combinations of particular and preferred groups unlessstated otherwise.

General Synthesis

Compounds of this invention can be made by the methods depicted in thereaction scheme shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thisinvention can be synthesized, and various modifications to these schemescan be made and will be suggested to one skilled in the art havingreferred to this disclosure. The starting materials and theintermediates of the reaction may be isolated and purified if desiredusing conventional techniques, including but not limited to filtration,distillation, crystallization, chromatography and the like. Suchmaterials may be characterized using conventional means, includingphysical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., more preferably from about 0° C. to about 125° C.and most preferably at about room (or ambient) temperature, e.g., about20° C.

Compounds of Formula (I) where X is —O— or —S(O)_(n)— where n is 0 to 2and other groups are as described in the Summary of the Invention can beprepared by the procedure illustrated and described in Scheme A below.

Reaction of a compound of formula I where R is alkyl, X is —O— or —S—and Ar¹ is as defined in the Summary of the Invention with anaminoalcohol of formula 2 where PG is a suitable amino protecting groupprovides a compound of formula 3. The reaction is carried out in thepresence of triphenylphosphine and diisopropyl azodicarboxylate in asuitable organic solvent such as tetrahydrofuran, and the like.

Compounds of formula I such as methyl 4-hydroxybenzoate, methyl4-mercaptobenzoate, and methyl 3-hydroxyisoxazole-5-carboxylate arecommercially available. Compounds of formula 2 can be prepared fromcommercially available aminoalcohols by reacting the amine with asuitable amino protecting group such as benzyloxycarbonyl,tert-butoxycarbonyl and the like under reaction conditions well known inthe art. A detailed description of suitable amino protecting groups andreaction conditions for their preparation can be found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981 theteaching of which is incorporated herein by reference in its entirety.Aminoalcohols such as 2-ethanolamine, 2-amino-1-propanol,2-methylaminoethanol, 2-amino-2-methyl-1-propanol, 2-amino-1-propanol,4-amino-2-butanol, and 1-amino-2-butanol are commercially available.Alternatively, compounds of formula 2 can be prepared from commerciallyavailable aminoacids by protecting the amino group with a suitableprotecting group followed by reduction of the acid group to the hydroxygroup with a suitable reducing agent under conditions well known in theart. If compounds of Formula (I) where X is —SO₂— are desired, thecorresponding compound of formula 3 where X is —S— can be treated withan oxidizing agent such as OXONE®, m-chloroperbenzoic acid, and thelike.

Removal of the amino protecting group in 3 provides a compound offormula 4. The reaction conditions employed for removal of the aminoprotecting group depend on the nature of the protecting group. Forexample, if the protecting group is tert-butoxycarbonyl, it is removedunder acid reaction conditions. Suitable acids are trifluoroacetic acid,hydrochloric acid, and the like in a suitable organic solvent such asmethanol, dioxane, tetrahydrofuran, and the like. If the protectinggroup is benzyl or benzyloxycarbonyl, it is removed under catalytichydrogenation reaction conditions. Suitable catalyst are palladium basedcatalysts and others known in the art. Other suitable reactionconditions for their removal can be found in T. W. Greene, ProtectingGroups in Organic Synthesis, John Wiley & Sons, Inc. 1981. The reactionis carried out in an inert organic solvent methylene chloride,tetrahydrofuran, dioxane, and the like.

Reaction of 4 with an acid or acid derivative (e.g., acid halide) offormula Ar²-COZ where Z is hydroxy or halo provides a compound offormula 5. Again, the reaction conditions employed depend on the natureof the Z group. If Z is hydroxy, the reaction is typically carried outin the presence of a suitable coupling agent e.g.,benzdtriazole-1-yloxy-trispyrrolidino-phosphonium hexafluorophosphate(PyBOP®), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HBTU),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl),or 1,3-dicyclohexylcarbodiimide (DCC), optionally in the presence of1-hydroxybenzotriazole hydrate (HOBT.H₂O), and a base such asN,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and thelike. The reaction is typically carried out at 20 to 30° C., preferablyat about 25° C., and requires 2 to 24 hours to complete. Suitablereaction solvents are inert organic solvents such as halogenated organicsolvents (e.g., methylene chloride, chloroform, and the like),acetonitrile, N,N-dimethylformamide, ethereal solvents such astetrahydrofuran, dioxane, and the like. Preferably, the reaction iscarried out with HOBt.H₂O, EDC.HCl in dichloromethane orN,N-dimethylformamide.

When Ar²COZ is an acid halide, the reaction is carried out in thepresence of a suitable base (e.g. triethylamine, diisopropylethylamine,pyridine, and the like). Suitable reaction solvents are polar organicsolvents such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide(DMF), dichloromethane, or any suitable mixtures thereof. The acidhalide such as acid chloride can be prepared by reacting thecorresponding acids with a halogenating agent such as oxalyl chloride,thionyl chloride, phosphorus oxychloride, and the like. Acids of formulaAr²COZ are either commercially available or they can be prepared fromcommercially available starting materials by methods known in the art.For example, benzoic acid, cinnamic acid, phenylacetic acid, nicotinicacid, isonicotinic acid, 3-methylbenzofuran-2-carboxylic acid, andbenzofuran-2-carboxylic acid are commercially available. Others such as3-phenoxymethylbenzofuran-2-carboxylic acid can be readily prepared fromcommercially available 3-methylbenzofuran-2-carboxylic acid by firstconverting it to 2-bromomethylbenzofuran-2-carboxylic acid (brominatingit with N-bromosuccinimide under conditions well known in the art)followed by reacting with phenol. Compound 5 where R³ is hydrogen canoptionally be converted to a corresponding compound of formula 5 whereR³ is other than hydrogen by reacting it with an alkylating agent underconditions well known in the art.

Compound 5 is then converted to a compound of Formula (I) by reacting itwith aqueous hydroxylamine in the presence of a base such as sodiumhydroxide and a mixture of organic solvents such as tetrahydrofuran andmethanol. Alternatively, the acid group in 5 is first activated with asuitable coupling agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl),or 1,3-dicyclohexylcarbodiimide (DCC), optionally in the presence of1-hydroxybenzotriazole hydrate (HOBT.H₂O) in a suitable organic solventsuch as dimethylformamide, and the like, and then reacted withhydroxylamine hydrochloride in the presence of a base such asN,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and thelike. Compounds of Formula (I) can also be prepared from compound 5 bythe methods disclosed in U.S. Pat. No. 5,998,412, the disclosure ofwhich is incorporated herein by reference in its entirety.

A compound of Formula (I) can be converted to other compounds of Formula(I). For example, a compound of Formula (I) where Ar¹ is phenylene, X is—O—, Y is ethylene, Ar² is 3-dimethylaminomethylbenzofuran-2-yl, R¹ andR³ are hydrogen can be prepared by reacting a compound of formula 4where Ar¹ is phenylene, X is —O—, Y is ethylene, and R is alkyl with3-methylbenzofuran-2-carboxylic acid as described above to give acompound of formula 5 where Ar² is 3-methylbenzofuran-2-yl. Brominationof the methyl group with a suitable brominating agent such asN-bromosuccinimide, followed by reaction with dimethylamine provides thecorresponding 3-dimethylaminobenzofuran-2-yl compound which is thenconverted to the desired compound under the reaction conditionsdescribed above.

Utility

The compounds of this invention are inhibitors of histone deacetylaseenzymes and are therefore useful in the treatment of proliferativediseases such as cancer such as lung, colon, AML, MML, skin, breast,ovarian, prostate, liver, brain and skin, psoriasis, fibroproliferativedisorder such as liver fibrosis, smooth muscle proliferative disordersuch as atherosclerosis and restenosis, inflammatory diseases such asarthritis, diseases involving angiogenesis such as cancer, diabeticretinopathy, haematopoietic disorder such as anaemia, fungal, parasiticand bacterial infections, viral infection, autoimmune diseases such asarthritis, multiple sclerosis, lupus, allergies, asthma, allergicrhinitis, and organ transplant, and bipolar disorders. Additionally, thecompounds of the present invention are useful in the treatment ofhepatitis C infection.

Testing

The ability of the compounds of this invention to inhibit histonedeacetylase enzymes can be tested in vitro and in vivo assays describedin biological assays Example 1 and 2 below. The hcv activity of thecompounds of this invention was tested in a hcv replicon assay atGeorgetown University. The compounds can also be tested for hcv activityutilizing the replicon assay described in Korner, V. L. et al., Science1999 Jul. 2:285 (5424):110-3.

Administration and Pharmaceutical Compositions

In general, the compounds of this invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of this invention, i.e., the active ingredient,will depend upon numerous factors such as the severity of the disease tobe treated, the age and relative health of the subject, the potency ofthe compound used, the route and form of administration, and otherfactors.

Therapeutically effective amounts of compounds of Formula (I) may rangefrom approximately 0.1-50 mg per kilogram body weight of the recipientper day; preferably about 0.5-20 mg/kg/day. Thus, for administration toa 70 kg person, the dosage range would most preferably be about 35 mg to1.4 g per day.

In general, compounds of this invention will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral orparenteral using a convenient daily dosage regimen, which can beadjusted according to the degree of affliction. Oral compositions cantake the form of tablets, pills, capsules, semisolids, powders,sustained release formulations, solutions, suspensions, elixirs,aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of in general, a compound of Formula (I)in combination with at least one pharmaceutically acceptable excipient.Acceptable excipients are non-toxic, aid administration, and do notadversely affect the therapeutic benefit of the compound of Formula (I).Such excipient may be any solid, liquid, semi-solid or, in the case ofan aerosol composition, gaseous excipient that is generally available toone of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 18^(th) ed., 1990).

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt% of a compound of Formula (I) based on the total formulation, with thebalance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1-80 wt %.Representative pharmaceutical formulations containing a compound ofFormula (I) are described below.

As stated previously, the compounds of this invention can beadministered in combination with known anti-cancer agents. Such knownanti-cancer agents include the following: estrogen receptor modulators,androgen receptor modulators, retinoid receptor modulators, cytotoxicagents, antiproliferative agents, prenyl-protein transferase inhibitors,HMG-CoA reductase inhibitors, HIV protease inhibitors, reversetranscriptase inhibitors, DNA methyl tranferase inhibitors, and otherangiogenesis inhibitors. The compound of the present invention compoundsare particularly useful when administered in combination with radiationtherapy. Preferred angiogenesis inhibitors are selected from the groupconsisting of a tyrosine kinase inhibitor, an inhibitor ofepidermal-derived growth factor, an inhibitor of fibroblast-derivedgrowth factor, an inhibitor of platelet derived growth factor, an MMP(matrix metalloprotease) inhibitor, an integrin blocker, interferon-α,interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor,carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, and an antibody to VEGF.

Preferred estrogen receptor modulators are tamoxifen and raloxifene.

“Estrogen receptor modulators” refers to compounds that interfere orinhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic agents” refer to compounds which cause cell death primarilyby interfering directly with the cell's functioning or inhibit orinterfere with cell myosis, including alkylating agents, tumor necrosisfactors, intercalators, microtubulin inhibitors, and topoisomeraseinhibitors.

Examples of cytotoxic agents include, but are not limited to,tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine,carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosilate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine) platinum, benzylguanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]-tetrachloride,diarizidinyispermine, arsenic trioxide,1-(11-odecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032).

Examples of microtubulin inhibitors include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)-ethyl]-(20S)camptothecin, BNP1350,BNPI100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)colchic(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)-amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine oefosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]-adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid ester,swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferativeagents” also includes monoclonal antibodies to growth factors, otherthan those listed under “angiogenesis inhibitors”, such as trastuzumab,and tumor suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which haveinhibitory activity for HMG-CoA reductase can be readily identified byusing assays well-known in the art. For example, see the assaysdescribed or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131at pp. 30-33. The terms “HMG-CoA reductase inhibitor” and “inhibitor ofHMG-CoA reductase” have the same meaning when used herein. It has beenreported that (Int. J. Cancer, 20;97(6):746-50, 2002) combinationtherapy with lovastatin, a HMG-CoA reductase inhibitor, and butyrate, aninducer of apoptosis in the Lewis lung carcinoma model in mice showedpotentiating antitumor effects

Examples of HMG-CoA reductase inhibitors that may be used include butare not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938;4,294,926; 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos.4,444,784; 4,820,850; 4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat.Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589),fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772; 4,911,165;4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), atorvastatin(LIPITOR®; see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691;5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; seeU.S. Pat. No. 5,177,080). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (Feb. 5, 1996) and U.S. Pat.Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor asused herein includes all pharmaceutically acceptable lactone andopen-acid forms (i.e., where the lactone ring is opened to form the freeacid) as well as salt and ester forms of compounds which have HMG-CoAreductase inhibitory activity, and □olchicin the use of such salts,esters, open-acid and lactone forms is included within the scope of thisinvention.

In HMG-CoA reductase inhibitors where an open-acid form can exist, saltand ester forms may preferably be formed from the open-acid, and allsuch forms are included within the meaning of the term “HMG-CoAreductase inhibitor” as used herein. Preferably, the HMG-CoA reductaseinhibitor is selected from lovastatin and simvastatin, and mostpreferably simvastatin.

Herein, the term “pharmaceutically acceptable salts” with respect to theHMG-CoA reductase inhibitor shall mean non-toxic salts of the compoundsemployed in this invention which are generally prepared by reacting thefree acid with a suitable organic or inorganic base, particularly thoseformed from cations such as sodium, potassium, aluminum, calcium,lithium, magnesium, zinc and tetramethylammonium, as well as those saltsformed from amines such as ammonia, ethylenediamine, N-methylglucamine,lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenzimidazole, diethylamine,piperazine, and tris(hydroxymethyl)aminomethane. Further examples ofsalt forms of HMG-CoA reductase inhibitors may include, but are notlimited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium hydroxyl, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, hydroxyl, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-CoA reductase inhibitor compoundsmay act as prodrugs which, when absorbed into the bloodstream of awarm-blooded animal, may cleave in such a manner as to release the drugform and permit the drug to afford improved therapeutic efficacy.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase). Examples of prenyl-protein transferase inhibiting compoundsinclude(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)quinolinone,(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)-methyl)-2-piperazinone,5(S)-n-butyl-1-(2-methylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-piperazinone,1-(2,2-diphenylethyl)-3-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine,4-{5-[4-hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{3-[4-(2-oxo-2H-pyridin-1-yl)benzyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-{3-[4-(5-chloro-2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-{3-[4-(2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl}benzonitrile,18,19-dihydro-19-oxo-5H,17H-6,10:12,16-dimetheno-1H-imidazo[4,3-c][1,11,4]dioxa-azacyclononadecine-9-carbonitrile,(±)-19,20-dihydro-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]-oxatriaza-cyclooctadecine-9-carbonitrile,19,20-dihydro-19-oxo-5H,17H-18,21-ethano-6,10:12,16-dimetheno-22H-imidazo[3,4-h][1,8,11,14]oxatriazacyclo-eicosine-9-carbonitrile,and(±)-19,20-dihydro-3-methyl-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxa-triazacyclooctadecine-9-carbonitrile.

Other examples of prenyl-protein transferase inhibitors can be found inthe following publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510,5,589,485, 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see J. Of Cancer,Vol. 35, No. 9, pp. 1394-1401 (1999).

Examples of HIV protease inhibitors include amprenavir, abacavir,CGP-73547, CGP-61755, DMP450, indinavir, nelfinavir, tipranavir,ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232, 632. Examples ofreverse transcriptase inhibitors include delaviridine, efavirenz,GS-840, HB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddI. It hasbeen reported (Nat. Med.; 8(3):225-32, 2002) that HIV proteaseinhibitors, such as indinavir or saquinavir, have potent anti-angiogenicactivities and promote regression of Kaposi sarcoma

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR20), inhibitors of epidermal-derived,fibroblast-derived, or platelet derived growth factors, MMP (matrixmetal loprotease) inhibitors, integrin blockers, interferon-∝,interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors,including nonsteroidal anti-inflammatories (NSAIDs) like aspirin andibuprofen as well as selective cyclooxygenase-2 inhibitors likecelecoxib, valecoxib, and rofecoxib (PNAS, Vol. 89, p. 7384 (1992);JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p. 573 (1990);Anat. Rec., Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83(1995); Clin., Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol., Vol16, p. 107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); CancerRes., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J.Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116(1999)), carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab.Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, NatureBiotechnology, Vol. 17, pp. 963-968 (October 1999); Kim et al., Nature,362, 841-844 (1993); WO 00/44777; and WO 00/61186).

As described above, the combinations with NSAID's are directed to theuse of NSAID's which are potent COX-2 inhibiting agents. For purposes ofthis specification an NSAID is potent if it possess an IC₅₀ for theinhibition of COX-2 of 1 μM or less as measured by the cell ormicrosomal assay known in the art.

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by the cell or microsomal assay disclosed hereinunder. Suchcompounds include, but are not limited to those disclosed in U.S. Pat.No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issuedJan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat.No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr.25, 1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995, U.S. Pat. No.5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug.27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No.5,698,584, issued Dec. 16, 1997, U.S. Pat. No. 5,710,140, issued Jan.20, 1998, WO 94/15932, published Jul. 21, 1994, U.S. Pat. No. 5,344,991,issued Jun. 6, 1994, U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S.Pat. No. 5,380,738, issued Jan. 10, 1995, U.S. Pat. No. 5,393,790,issued Feb. 20, 1995, U.S. Pat. No. 5,466,823, issued Nov. 14, 1995,U.S. Pat. No. 5,633,272, issued May 27, 1997, and U.S. Pat. No.5,932,598, issued Aug. 3, 1999, all of which are hereby incorporated byreference. Other examples of specific inhibitors of COX-2 include thosedisclosed in U.S. Pat. No. 6,313,138 the disclosure of which isincorporated herein by reference in its entirety.

General and specific synthetic procedures for the preparation of theCOX-2 inhibitor compounds described above are found in U.S. Pat. No.5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan.19, 1999, and U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, all ofwhich are herein incorporated by reference.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to, the following:

or a pharmaceutically acceptable salt thereof.

Compounds which are described as specific inhibitors of COX-2 and aretherefore useful in the present invention, and methods of synthesisthereof, can be found in the following patents, pending applications andpublications, which are herein incorporated by reference: WO 94/15932,published Jul. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994,U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738,issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995,U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272,issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999.

Compounds which are specific inhibitors of COX-2 and are thereforeuseful in the present invention, and methods of synthesis thereof, canbe found in the following patents, pending applications andpublications, which are herein incorporated by reference: U.S. Pat. No.5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan.19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No.6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr. 25,1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995, U.S. Pat. No.5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug.27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No.5,698,584, issued Dec. 16, 1997, and U.S. Pat. No. 5,710,140, issuedJan. 20, 1998.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpimase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]-methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonyl-imino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counter-act binding of a physiological ligand to the α_(v)β₅integrin, to compounds which antagonize, inhibit or counteract bindingof a physiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆;α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈,α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, ST1571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, SU11248,STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, andEMD121974.

The instant compounds are also useful, alone or in combination withplatelet fibrinogen receptor (GP Iib/IIIa) antagonists, such astirofiban, to inhibit metastasis of cancerous cells. Tumor cells canactivate platelets largely via thrombin generation. This activation isassociated with the release of VEGF. The release of VEGF enhancesmetastasis by increasing extravasation at points of adhesion to vascularendothelium (Amirkhosravi, Platelets 10, 285-292, 1999). Therefore, thepresent compounds can serve to inhibit metastasis, alone or incombination with GP Iib/IIIa) antagonists. Examples of other fibrinogenreceptor antagonists include abciximab, eptifibatide, sibrafiban,lamifiban, lotrafiban, cromofiban, and CT50352.

“DNA methyltransferase inhibitor” refers to compounds which inhibit themethylation of the DNA base cytosine at the C-5 position of that base bythe DNA methyltransferase enzyme. Examples of such DNA methyltransferaseinhibitor include compounds disclosed in U.S. Pat. Nos. 6,329,412 and6,268,137. Specific DNA methyltransferase inhibitors include5-azacytosine and zebularine®.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described above andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The term administration and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The compounds of the instant invention may also be co-administered withother well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the compounds of the instant invention may also beco-administered with other well known cancer therapeutic agents that areselected for their particular usefulness against the condition that isbeing treated. Included in such combinations of therapeutic agents arecombinations of the farnesyl-protein transferase inhibitors disclosed inU.S. Pat. No. 6,313,138 and an antineoplastic agent. It is alsounderstood that such a combination of antineoplastic agent and inhibitorof farnesyl-protein transferase may be used in conjunction with othermethods of treating cancer and/or tumors, including radiation therapyand surgery.

Examples of an antineoplastic agent include, in general,microtubule-stabilizing agents (such as paclitaxel (also known asTaxol®), docetaxel (also known as Taxotere®, epothilone A, epothilone B,desoxyepothilone A, desoxyepothilone B or their derivatives);microtubule-disruptor agents; alkylating agents, anti-metabolites;epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor;procarbazine; mitoxantrone; platinum coordination complexes; biologicalresponse modifiers and growth inhibitors; hormonal/anti-hormonaltherapeutic agents and haematopoietic growth factors.

Example classes of antineoplastic agents include, for example, theanthracycline family of drugs, the vinca drugs, the mitomycins, thebleomycins, the cytotoxic nucleosides, the taxanes, the epothilones,discodermolide, the pteridine family of drugs, diynenes and thepodophyllotoxins. Particularly useful members of those classes include,for example, doxorubicin, caminomycin, daunorubicin, aminopterin,methotrexate, methopterin, dichloromethotrexate, mitomycin C,porfiromycin, Herceptin®, Rituxan®, 5-fluorouracil, 6-mercaptopurine,gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxinderivatives such as colchicines, etoposide, etoposide phosphate orteniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine,leurosine, paclitaxel and the like. Other useful antineoplastic agentsinclude estramustine, cisplatin, carboplatin, cyclophosphamide,bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine,thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine,L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide,flutamide, leuprolide, pyridobenzoindole derivatives, interferons andinterleukins. The preferred class of antineoplastic agents is thetaxanes and the preferred antineoplastic agent is paclitaxel.

Radiation therapy, including x-rays or gamma rays that are deliveredfrom either an externally applied beam or by implantation of tinyradioactive sources, may also be used in combination with the compoundsof this invention alone to treat cancer.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Synthetic Examples Example 1 Synthesis ofN-hydroxy-4-(2-benzenecarbonylamino-ethoxy)benzamide

Step 1

To a solution of 2-aminoethanol (3.1 g, 50 mmol) in THF (10 ml) wasadded tert-butyloxycarbonyl anhydride (10.9 g, 50 mmol) in THF (150 ml).The reaction mixture was stirred for 3 h, then diluted with ethylacetate, washed with 0.5 M aqueous HCl, and brine. The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo to give2-N-Boc-aminoethanol which was directly used in the next step.

Step 2

To a solution of triphenylphosphine (17.7 g, 67.5 mmol) in anhydrous THF(135 ml) was added DIAD (13.6 g, 67.5 mmol). The solution was stirreduntil a white precipitate was formed (2 to 10 min). After additional 60min., a solution of 2-N-Boc aminoethanol (7.2 g, 45 mmol) and methyl4-hydroxybenzoate (6.8 g, 45 mmol) in THF (25 ml) was added and stirringwas continued for 5 h. The reaction mixture was concentrated in vacuoand purified by flash chromatography to give methyl 4-(2-N-Bocaminoethoxy)benzoate. Alternatively, the crude material can directly beused in the next step.

Step 3

To a solution of crude methyl 4-(2-N-Boc aminoethoxy)benzoate inmethanol (20 ml) was added 4M HCl/dioxane (180 ml). After stirring for 3h, diethyl ether (300 ml) was added providing a white precipitate. Thesolid was collected, suspended in ethyl acetate and stirred for 15-20min. The solid was collected again and dried under high vacuo providingmethyl 4-(2-aminoethoxy)benzoate hydrochloride 6.3 g (60% over 2 steps).

Step 4

To a suspension of methyl 4-(2-amino-ethoxy)benzoate hydrochloride(0.232 g, 1 mmol) in THF (6 ml) was added benzoyl chloride (0.140 g, 1mmol) followed by triethylamine (0.121 g, 1.2 mmol). The reactionmixture was stirred for 1 h and then diluted with ethyl acetate. Theorganic layer was washed with 0.5 M aqueous HCl, saturated sodiumbicarbonate solution, and brine. The organic layer was concentrated invacuo to give methyl 4-(2-benzenecarbonylamino-ethoxy)benzoate which wasdirectly used in the next step.

Step 5

To a solution of crude methyl 4-(2-benzenecarbonylamino-ethoxy)benzoate(0.5 mmol) in a 1:1 mixture of THF/methanol (20 ml) was added 50 wt. %aqueous hydroxylamine (3 ml) followed by 1M aqueous NaOH (1 ml)adjusting the pH between 10-11. The reaction mixture was stirred for 14h, neutralized to pH=7-8 with 6 M aqueous HCl and concentrated in vacuo.The precipitate was collected and purified by HPLC providing the titlecompound as a white solid. ¹H NMR (DMSO-d₆): δ 8.69 (t, J=5.8 Hz, 1H),7.83 (d, J=7.5 Hz, 2H), 7.69 (d, J=9.1 Hz, 2H), 7.46 (m, 3H), 6.99 (d,J=9.1 Hz, 2H), 4.16 (t, J=5.8 Hz, 2H), 3.63 (q, J=5.8 Hz, 2H). EM(calc.): 300.1; MS (ESI) m/e: 301.1 (M−1)⁺, 299.0 (M+1)⁻.

Proceeding as described in Example 1, Steps 1-4 above, but substituting2-aminoethanol with (S)-(+)-2-amino-1-butanol provided methyl4-(2S-aminobutoxy)benzoate hydrochloride.

Example 2 Synthesis ofN-hydroxy-4-[2-(benzofuran-2-yl-carbonylamino)-ethoxy]-benzamide

Step 1

A mixture of benzofuran-2-carboxylic acid (0.162 g, 1 mmol), EDC.HCl(0.268 g, 1.4 mmol) and HOBT.H₂O (0.203 g, 1.5 mmol) in DMF (6 ml) wasstirred for 2 h. Methyl 4-(2-aminoethoxy)benzoate hydrochloride (0.232g, 1 mmol) was added followed by triethylamine (0.121 g, 1.2 mmol). Thereaction mixture was stirred for 2 h and then diluted with ethylacetate, washed with saturated sodium bicarbonate solution, and brine.The organic layer was concentrated in vacuo and the crude4-[2-(benzofuran-2-ylcarbonylamino)ethoxy]-benzoate was converted to thetitle compound as described in Example 1, Step 5 above. ¹H NMR (DMSO-d₆)δ 11.05 (s, 1H), 8.92 (t, J=5.6 Hz, 1H), 8.88 (s, 1H), 7.76 (d, J=8.0Hz, 1H), 7.70 (d, J=9.2 Hz, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.55 (s, 1H),7.46 (t, J=6.8 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.01 (d, J=8.2 Hz, 2H),4.18 (t, J=5.6 Hz, 2H), 3.67 (m, 2H). EM (calc.): 340.1; MS (ESI) m/e:(M+1H)⁺: 341.0, (M−1H)⁻: 339.1.

Example 3 Synthesis ofN-hydroxy-4-[2-(benzothiophen-2-yl-carbonylamino)-ethoxy]-benzamide

To a suspension of methyl 4-(2-aminoethoxy)benzoate hydrochloride (0.232g, 1 mmol) in THF (6 ml) was added benzothiophene-2-carbonyl chloride(0.150 g, 1 mmol) followed by triethylamine (0.121 g, 1.2 mmol). Thereaction mixture was stirred for 1 h and diluted with ethyl acetate (50ml). The organic layer was washed with 0.5 M aqueous HCl, saturatedsodium bicarbonate solution, and brine. The organic layer wasconcentrated in vacuo and the crude methyl4-[2-(benzothiophen-2-yl-carbonylamino)ethoxy]benzoate was converted tothe title compound as described in Example 1, Step 5 above.

Proceeding as described in Example 3 above, but substituting methyl4-(2-aminoethoxy)benzoate hydrochloride with methyl4-(2S-aminobutoxy)benzoate hydrochloride and benzothiophene-2-carbonylchloride with cinnamoyl chloride providedN-hydroxy-4-[2S-(trans-cinnamoylamino)butoxy]benzamide.

Example 4 Synthesis ofN-hydroxy-4-[2-(3-dimethylaminobenzofuran-2-ylcarbonylamino)-ethoxy]-benzamide

Step 1

To a solution of 3-methyl-benzofuran-2-carboxylic acid (0.98 g, 5.6mmol) and 5 drops of DMF in THF (25 ml) was added oxalyl chloride (0.53ml, 6.1 mmol). After stirring the solution for 1 h at room temperature,methanol (20 ml) and TEA (7 ml) were added. The slurry was stirredovernight at room temperature, then concentrated and dissolved in ethylacetate (100 ml) and washed with mild NaHCO₃ (100 ml). The organic layerwas dried (MgSO₄), filtered and concentrated to collect3-methylbenzofuran-2-carboxylic acid methyl ester (1 g) as a tan solid.The crude methyl ester was used without further purification.

Step 2

A solution of 3-methylbenzofuran-2-carboxylic acid methyl ester (1.0 g,5.3 mmol), NBS (0.95 g, 5.3 mmol) and AIBN (87 mg, 0.53 mmol) was heatto reflux in CCl₄ (40 ml) for 3 h, then cooled to room temperature andconcentrated. The residue was dissolved in ethyl acetate (100 ml) andwashed with water (100 ml). The organic layer was dried (MgSO₄),filtered and concentrated to collect3-bromomethylbenzofuran-2-carboxylic acid methyl ester (1.55 g) of atan/yellow solid which was used in the next step without furtherpurification.

Step 3

3-Bromomethylbenzofuran-2-carboxylic acid methyl ester (269 mg, 1 mmol)was dissolved in anhydrous DMF and added 2M dimethylamine/THF solution(1.5 ml, 3 mmol). After 1-2 h, the reaction was diluted with EtOAc andwashed twice with saturated NaHCO₃ (aq.) and brine. The organic extractover was dried over Na₂SO₄ and then concentrated in vacuo. The crude waspurified on a silica gel column (5% MeOH in dichloromethane) to give3-dimethylaminomethylbenzofuran-2-carboxylic acid methyl ester (131 mg).

Step 4

To a solution of 3-dimethylaminomethylbenzofuran-2-carboxylic acidmethyl ester (131 mg, 0.56 mmol) in MeOH was added 1N NaOH(aq.) till thepH of the solution was 13. The reaction mixture was stirred for 60-90min. Upon completion, the reaction mixture was acidified to pH 3 withHCl (aq.) and concentrated to dryness to give3-dimethylaminomethylbenzofuran-2-carboxylic acid as the HCl salt, whichwas used for next step without further purification.

Step 5

To 3-dimethylaminomethylbenzofuran-2-carboxylic acid (140 mg, 0.56 mmol)was added EDC.HCl (150 mg, 0.784 mmol) and HOBt.H₂O (114 mg, 0.84 mmol)in anhydrous DMF. The reaction mixture was stiffed for 30-60 min., afterwhich methyl-(4-(2-ethoxyamine))benzoate hydrochloric salt (130 mg, 0.56mmol) and triethylamine (94 μL, 0.672 mmol) were added and the reactionwas stirred overnight. The reaction mixture was diluted with EtOAc andwashed twice with saturated NaHCO₃ (aq.) and brine. The organic extractwas concentrated in vacuo to give methyl4-[2-(3-dimethylaminobenzofuran-2-yl-carbonylamino)ethoxy]benzoate,which was then used without further purification.

Step 6

To a solution of crude methyl4-[2-(3-dimethylaminobenzofuran-2-yl-carbonylamino)-ethoxy]-benzoate inMeOH and THF was added excess aqueous hydroxylamine solution andNaOH(aq.) to give pH 10-11. The reaction mixture was stirred overnightand then neutralized to pH 7-8 with aqueous hydrochloric acid andconcentrated in vacuo. The residue was dissolved in acetonitrile andwater and purified with prep HPLC to give the title compound (107 mg).¹NMR (400 MHz, DMSO-d₆) δ 9.88 (m, 1H), 9.31 (t, J=6.0 Hz, 1H), 8.04 (d,J=7.6 Hz, 1H), 7.70 (m, 3H), 7.57 (t, J=7.6 Hz, 1H), 7.45 (t, J=7.6 Hz,1H), 6.99 (d, J=9.2 Hz, 2H), 4.76 (d, J=4.8 Hz, 2H), 4.23 (t, J=6.0 Hz,2H), 3.71 (m, 2H), 2.84 (s, 3H), 2.83 (s, 3H). EM (calc.): 397.2; MS(ESI) m/e (M+1H)⁺: 398.1, (M−1H)⁻: 396.2.

Example 5 Synthesis ofN-hydroxy-4-{2-[3-(2,2,2-trifluoroethyloxymethyl)benzofuran-2-yl-carbonylamino]ethoxy}benzamide

Step 1

Sodium hydride (15 mg, 0.56 mmol) was suspended in anhydrous DMF andstirred under N₂(g). 2,2,2-Trifluoroethanol (270 μL, 3.7 mmol) was addedand after stirring the reaction mixture for 15-20 min.,3-bromomethylbenzofuran-2-carboxylic acid methyl ester was added. After8 h, 1N NaOH (aq.) was added and the reaction mixture was stirred for10-15 min. The reaction mixture was acidified reaction to pH 3 withaqueous hydrochloric acid and the product was extracted with EtOAc. Theorganic layer was dried organic over Na₂SO₄ and concentrated in vacuo togive 3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-carboxylic acid (38 mg)which was then used without purification.

Step 2

To a solution of 3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-carboxylicacid (38 mg, 0.139 mmol) in anhydrous DMF was added EDC.HCl (37 mg,0.195 mmol) and HOBt.H₂O (26 mg, 0.195 mmol). After 60-90 min.,methyl-(4-(2-ethoxyamine))benzoate hydrochloric salt (32 mg, 0.139 mmol)and triethylamine (23 μL, 0.167 mmol) were added and the reactionmixture was stirred for 1-2 h. The reaction mixture was diluted withEtOAc and washed twice with saturated NaHCO₃(aq.) and the organicextract was concentrated to give methyl4-{2-[3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-yl-carbonylamino]ethoxy}-benzoate,which was then used without further purification.

Step 3

4-{2-[3-(2,2,2-Trifluoroethoxymethyl)benzofuran-2-yl-carbonylamino]-ethoxy}-benzoatewas dissolved in MeOH and excess aqueous hydroxylamine solution andNaOH(aq) were added to give pH 10-11. After stirring overnight, thereaction mixture was neutralized reaction to pH 7-8 with aqueoushydrochloric acid. The reaction mixture was concentrated in vacuo togive a solid which was collected and washed with water, then dissolvedin acetonitrile and water and purified with prep HPLC to give the titlecompound (35 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.95 (t,J=5.6 Hz, 1H), 8.89 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.8 Hz,2H), 7.63 (d, J=8.8 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.36 (t, J=8.0 Hz,1H), 7.00 (d, J=9.2 Hz, 2H), 5.25 (s, 2H), 4.18 (m, 4H), 3.67 (m, 2H).EM (calc.): 452.1; MS (ESI) m/e (M+1H)⁺: 453.0, (M−1H)⁻: 451.0.

Example 6 Synthesis ofN-hydroxy-4-{2-[5-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-yl-carbonylamino]ethoxy}benzamide

Step 1

5-Methoxybenzofuran-2-carboxylic acid (5.04 g, 26 mmol) was weighed intoa 200 ml round bottom flask fitted with a stir bar, septum and nitrogeninlet. Anhydrous MeOH (50 ml) was added under nitrogen atmosphere. Thesolution was cooled in an ice bath and thionyl chloride (2.3 ml, 32mmol) was added dropwise with vigorous stirring. After stirring for 72 hat room temperature, the reaction mixture was poured into water (150 ml)and the white solid was collected. The solid was dissolved in toluene(100 ml) and the solution was washed with 1M NaHCO₃ and brine and driedover MgSO₄. Removal of the organic layer provided5-methoxybenofuran-2-carboxylic acid methyl ester as a white solid (5.15g).

Step 2

A solution of 5-methoxybenzofuran-2-carboxylic acid methyl ester (5.15g, 25 mmol) in anhydrous methylene chloride (15 ml) was cooled to −40°under nitrogen atmosphere. Boron tribromide in CH₂Cl₂ (27 ml of 1.0 M)was added over 1 h using a syringe pump. The reaction mixture wasallowed to warm to room temperature. After 16 h, the reaction mixturewas cooled in an ice bath and quenched with MeOH (15 ml). The reactionmixture was poured into brine (100 ml) and extracted with EtOAc. Theorganic extracts were dried over anhydrous MgSO₄, and the solvent wasremoved on rotary evaporator. The residue was triturated with hexane andthe yellow solid was filtered and dissolved in anhydrous MeOH (30 ml).The solution was cooled in an ice bath and thionyl chloride (1.9 ml, 26mmol) was added dropwise. After 72 h, water (100 ml) was added and solidwas collected. Purification of the crude product on a 300 cm³ silica gelin a 5×15 cm plug using EtOAc provided 5-hydroxy-benzofuran-2-carboxylicacid methyl ester (4.53 g).

Step 3

Anhydrous tetrahydrofuran (15 ml) was added to a mixture of5-hydroxybenzofuran-2-carboxylic acid methyl ester (1.10 g, 5.7 mmol),triphenylphosphine (1.50 g, 5.7 mmol), and1-(2-hydroxyethyl)-pyrrolidine (0.66 g, 5.7 mmol) under a nitrogenatmosphere. Diisopropyl azodicarboxylate (1.15 ml, 5.8 mmol) was slowlyadded to the solution at room temperature. After 2 days, the solvent wasremoved and the residue was dissolved in a 2:1 mixture of Et₂O:EtOAc(150 ml). The solution was washed with 1.0M aqueous NaOH. The productwas extracted into 1.0 M hydrochloric acid and the combined acidextracts were washed with Et₂O. The extracts were cooled and the pH ofthe extracts was adjusted to pH 12 with 50% aqueous NaOH. The basicsolution was extracted with CH₂Cl₂ and the organic layer was dried overanhydrous MgSO₄, and concentrated to give5-(2-pyrrolidin-1-yl-ethoxy)benzofuran-2-carboxylic acid methyl ester(0.96 g) as an amber colored solid.

Step 4

To an ice-cooled solution of5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid methyl ester(960 mg, 3.3 mmol) anhydrous ethylene glycol dimethyl ether (10 ml) wasadded dropwise degassed aqueous lithium hydroxide solution (2.0 ml,2.0M). After stirring at room temperature for 4 h, the solution wascooled down and the pH was adjusted to 2 with 4.0 M HCl in dioxane. Agummy tan precipitate formed. The solvent was removed and the gummyresidue was frozen and lyophilized. The tan colored solid was dissolvedin boiling 2-propanol (90 ml), the solution was filtered hot and thencooled to give 5-(2-pyrrolidin-1-yl-ethoxy)-benzofuran-2-carboxylic acidas beige colored needles (528 mg). Additional 153 mg was obtained fromthe mother liquor.

Step 5

To a solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid(156 mg, 0.50 mmol) and 4-(2-aminoethoxy)benzoic acid methyl esterhydrochloride (129 mg, 0.56 mmol) in DMF (4.5 ml) in a 20 ml vial wasadded diisopropylethylamine (0.88 ml, 5.1 mmol). A solution ofO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (740 μL, 0.82 M, 0.61 mmol) in DMF was added to givea bright yellow solution. The vial was purged with nitrogen and stirredat room temperature for 18 h. The solution was removed and the residuewas dissolved in EtOAc (25 ml) and washed with H₂O, 1.0M aqueous K₂CO₃,and brine. The organic layer was dried over anhydrous MgSO₄ and solventwas removed on a rotary evaporator. Purification of the residue bycolumn chromatography on a silica gel column using 93:5:2CH₂Cl₂:MeOH:TEA eluent provided4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoicacid methyl ester as a beige solid (174 mg).

Step 6

To a solution of4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoicacid methyl ester (169 mg, 0.37 mmol) in methanol (8 ml) andtetrahydrofuran (4 ml) was added hydroxylamine in water (2.9 ml of a 50wt. % solution) and 4.0 M aqueous solution of sodium hydroxide (0.65ml). After stirring for 18 h, the organics were removed and the aqueoussolution was cooled in an ice/water bath and the pH was adjusted to ˜8with 4.4 ml 1.0 M hydrochloric acid to give precipitates. Theheterogeneous solution was warmed to room temperature and acetonitrilewas added till the precipitates dissolved. The solution waschromatographed on C-18 reverse phase HPLC. Fractions with absorbance at214 nm, were collected, frozen, and lyophilize to give the titlecompound (31 mg). ¹H NMR (400 MHz, DMSO-d₆) δ: 11.05 (s, 1H), 10.4 (s,1H), 8.91 (s, 2H), 7.70 (d, 2H, J=7.4), 7.59 (dd, 1H, J=3.7, 9.1 Hz),7.51 (d, 1H, J=3.7 Hz), 7.35 (s, 1H), 7.13 (d, 1H, J=9.0 Hz), 7.00 (d,2H, J=7.4 Hz), 4.37 (m, 2H), 4.18 (m, 2H), 3.62 (m, 6H), 3.12 (m, 2H),2.02 (m, 2H), 1.89 (m, 2H). EM (calc.): 453.2; MS (ESI) m/e (M+1H)⁺:454.1, (M−1H)⁻: 452.2.

Example 7 Synthesis ofN-hydroxy-4-[2-(3-dimethylaminobenzofuran-2-ylcarbonylamino)-ethoxy]-benzamidehydrochloride

Step 1

(2-Hydroxyethyl)carbamic acid tert-butyl ester (152.0 g, 0.942 mol) and4-hydroxybenzoic acid methyl ester (174.0 g, 1.12 mol) were dissolved intetrahydrofuran (2000 ml) and cooled to 0-5° C. Triphenylphosphine(292.8 g 1.116 mol) was added to the cooled mixture. A solution ofdiisopropyl azodicarboxylate (246.0 g, 1.218 mol) in tetrahydrofuran(400 ml) was added dropwise over a period of one to two hours keepingthe reaction temperature below 10° C. After addition, the reaction wasallowed to warm slowly to ambient temperature and stirred overnight.After completion of reaction, solvent was distilled under reducedpressure and the resulting oil was dissolved in ethanol (500 ml) andethyl acetate (2000 ml). Acetyl Chloride (222.0 g, 2.826 mol) was addeddrop wise over fifteen minutes with the temperature allowed to rise to40° C. The resulting suspension was stirred at 40° C. until completionof reaction. After completion of reaction, the resulting crystals werefiltered on a coarse frit and washed with ethyl Acetate (300 mL). Thematerial is dried in vacuo to give of 4-(2-aminoethoxy)benzoic acidmethyl ester hydrochloride (204.1 g) as a white crystalline solid.

Step 2

4-(2-Aminoethoxy)benzoic acid methyl ester hydrochloride (78.90 g, 0.340mol) and 3-methylbenzofuran-2-carboxylic acid (60.0 g, 0.340 mol) weresuspended in acetonitrile (360 ml) and cooled to 0-5° C. Pyridine (137.6mL, 1.702 mol) was added quickly. A solution of phosphorous oxychloride(52.2 g, 0.340 mol) in acetonitrile (60 ml) was added drop wise overthirty to forty-five minutes with the temperature kept below 20° C. Thereaction mixture was allowed to stir for one hour and warm slowly toambient temperature. After completion of reaction, the solution wasadded to a rapidly stirred 0-5° C. mixture of chlorobenzene (1000 ml)and 1N hydrochloric acid (1000 ml). The reaction mixture was stirredrapidly and allowed to warm to room temperature. The organic layer waswashed with water, 3% potassium hydroxide, and again with water.Chlorobenzene (100 ml) was added to the washed organic layer. Solvent(100 ml) was then distilled at atmospheric pressure until the pottemperature reached 132° C. After cooling to ambient temperature,4-{2-[(3-methylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acid methylester was stored in solution for use in the next step.

Step 3

A solution of 4-{2-[(3-methylbenzofuran-2-carbonyl)amino]ethoxy}benzoicacid methyl ester (0.340 mol) in chlorobenzene (1000 ml) was treatedwith 2,2′-azobisisobutyronitrile (5.60 g, 0.017 mol) andN-bromosuccinimide (75.76 g, 0.426 mol). The resulting mixture is heatedto 80° C. and stirred for one hour. After completion of reaction, thereaction mixture was cooled to ambient temperature and washed withwater, 3% sodium hydrogensulfite, and again with water. Solvent wasdistilled under reduced pressure and after cooling to ambienttemperature, dichloromethane was added and to give4-{2-[(3-bromomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acidmethyl ester which was used in the next step.

Step 4

A solution of4-{2-[(3-bromomethylbenzofuran-2-carbonyl)amino]ethoxy}-benzoic acidmethyl ester (0.340 mol) in chlorobenzene (200 ml) and dichloromethane(800 ml) was added dropwise to a 0-5° C. solution of 2M dimethylamine intetrahydrofuran (510 ml, 1.022 mol) over 30 minutes with the temperaturebelow 20° C. The resulting mixture was stirred for one hour and allowedto warm to ambient temperature. After completion of reaction, thereaction mixture was washed with 5% potassium carbonate and water.Solvent was distilled at atmospheric pressure until the pot temperaturereached 100° C. After cooling to ˜50° C., acetonitrile (400 ml) andethyl Acetate (400 ml) were added to the pot. The reaction mixture washeated to reflux until all solids dissolved. The reaction mixture wasallowed to cool to give4-{2-[(3-dimethylaminomethyl-benzofuran-2-carbonyl)amino]ethoxy}benzoicacid methyl ester (76.6 g) as an off white powder.

Step 5

4-{2-[(3-Dimethylaminomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoicacid methyl ester (70.0 g, 0.177 mol) was suspended in methanol (350ml). 50% Potassium hydroxide (139.8 g, 1.062 mol) was added and thereaction mixture was heated to 60° C. until completion of reaction.After cooling to room temperature, the resulting crystals were filteredon a coarse frit and washed with methanol. The crystals were dried invacuo to give4-{2-[(3-dimethylaminomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoicacid potassium salt (72.0 g) as a white solid.

Step 6

4-{2-[(3-Dimethylaminomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoicacid potassium salt (20.0 g, 0.0476 mol) was suspended inN,N-Dimethylformamide (100 ml). 4 Molar hydrochloric acid in dioxane(11.9 ml, 0.0476 mol) was added to the suspension. After stirring forthirty minutes at ambient temperature, the reaction mixture was filteredthrough a medium frit. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (10.94 g, 0.0571 mol) and 1-hydroxybenzotriazole (7.71 g,0.0571 mol) were added to the solution and the reaction mixture wasstirred one hour at ambient temperature. In a separate pot,hydroxylamine hydrochloride (13.2 g, 1.904 mol) was suspended inN,N-dimethylformamide (100 ml) and treated with triethylamine (33.1 ml,2.380 mol). After stirring the reaction mixture for 1 h, the salt wasfiltered off and the resulting solution was added to the above activatedacid solution and stirred at ambient temperature until completion ofreaction. After the product began to crystallize, methanol (150 ml) wasadded slowly over thirty min. The reaction mixture was stirred for 1 hat ambient temperature then cooled to 0-5° C. and stirred another hour.The crystals were filtered and washed with methanol (40 ml) before beingdried in vacuo to give 3-dimethylaminomethylbenzofuran-2-carboxylic acid[2-(4-hydroxy-carbamoylphenoxy)ethyl]amide (11.88 g) as a white solid.The crude material (13.25 g, 0.033 mol) was suspended inN,N-dimethylformamide (80 ml) and heated to 100° C. to give a solution.After cooling, ethanol (80 ml) was added drop-wise over thirty minutesand the resulting suspension was allowed to cool for an hour. Thecrystals were filtered and washed with ethanol (40 ml) and dried to givepure product (9.82 g) as a white solid.

Step 7

N-hydroxy-4-[2-(3-dimethylaminobenzofuran-2-ylcarbonylamino)ethoxy]-benzamide(22.7 g, 0.057 mol) was suspended in 2-propanol (220 ml). 12 M HCl (5.2ml, 0.063 mol) was added in one portion and the resulting mixture washeated to reflux. Water (44 ml) was added dropwise until a homogenoussolution was obtained. The reaction mixture was allowed to cool andcrystallize overnight. After cooling below 5° C. for one h, the crystalswere filtered and washed with 2-propanol before being dried in vacuo togive the title compound (22.0 g) as a white solid.

Example 8 Synthesis ofN-hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)ethylsulfanyl]-benzamide

Step 1

To a solution of diisopropyl azodicarboxylate (DIAD, 4.04 g, 20 mmol) inTHF (100 ml) at 0° C. was added triphenylphosphine (5.25 g, 20 mmol).After 1 h, a solution of Boc-ethanolamine (3.22 g, 20 mmol) in THF (10ml) was added. After 20 min., a solution of methyl 4-mercaptobenzoate(3.86 g, 20 mmol) in THF (10 ml) was added and the reaction mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated and ethyl acetate (150 ml) was added. The solution waswashed with 1M HCl, saturated aqueous NaHCO₃, brine, dried over MgSO₄,filtered, and evaporated to dryness. The oily yellow residue was elutedthrough a plug of silica gel (0-20 ethyl acetate in hexane as mobilephase) and the product was then recrystallized from ether and hexane togive methyl 4-(2-tert-butoxycarbonylaminoethylsulfanyl)benzoate (4.00g).

Step 2

A solution of methyl 4-(2-tert-butoxycarbonylaminoethylsulfanyl)benzoate(1.00 g, 3.21 mmol) in dichloromethane (8 ml) was treated with asolution of HCl in dioxane (4M, 8 ml, 10 eq.) at room temperature for 3h. Ether (100 ml) was added and the mixture was filtered, washed withether and pumped dry to give methyl 4-(2-aminoethylsulfanyl)benzoatehydrochloride.

Step 3

Methyl 4-(2-aminoethylsulfanyl)benzoate hydrochloride (0.248 g, 1.00mmol), was combined with benzofuran-2-carboxylic acid (0.162 g, 1.00mmol) and HBTU (0.379 g, 1.00 mmol) in DMF (5 ml) at room temperature.Triethylamine (0.307 ml, 2.2 mmol) was added and the reaction mixturewas stirred at room temperature overnight. Saturated aqueous NaHCO₃ (15ml) was added to give precipitates which was broken up by the additionof water (20 ml). The solid was filtered and the cake was dissolved inethyl acetate. The residual water was removed by pipette and hexane wasadded to give methyl4-{2-[(benzofuran-2-yl-carbonyl)-amino]ethylsulfanyl}benzoate (0.138 g)as a gum which was used in the next step without further purification.

Step 4

To a solution of methyl4-{2-[(benzofuran-2-yl-carbonyl)amino]ethylsulfanyl}-benzoate in THF (2ml) was added a solution of 50% hydroxylamine in water (4 ml). Methanol(2 ml) and 0.1 M NaOH (0.1 ml) were added. The reaction mixture wasstirred for three days at room temperature. The solvents were evaporatedand the residue was crystallized from dichloromethane/ethyl acetate, togive the title compound (46 mg).

¹H NMR (DMSO-d⁶): 3.12 (2H, m); 3.5 (2H, m); 7.33 (1H, t); 7.42 (2H, d);7.45 (1H, m*); 7.53 (1H, s); 7.62 (1H, d); 7.7 (2H, d); 7.78 (1H, d);8.96 (1H, t); 8.99 (1H, br. s). MS (M+1): 357.

Example 9 Synthesis ofN-hydroxy-4-[2-(benzofuran-2-ylcarbonylamino)ethylsulfonyl]-benzamide

Step 1

To a solution of methyl4-(2-tert-butoxycarbonylaminoethylsulfanyl)-benzoate (3.00 g, 9.63 mmol)in methanol/water (1:1, 100 ml) was added Oxone® (13.03 g, 21.19 mmol).After 48 h, methanol was removed under reduced pressure, and the residuewas partitioned between ethyl acetate (150 ml) and saturated aqueousNaHCO₃ (150 ml). The organic phase was washed with brine (100 ml), driedover MgSO₄, filtered, concentrated in vacuo, and the residue wasrecrystallized from ethyl acetate/hexane to give methyl4-(2-tert-butoxycarbonylamino-ethanesulfonyl)benzoate (2.86 g) of theproduct.

Step 2

A solution of methyl4-(2-tert-butoxycarbonylaminoethanesulfonyl)benzoate (2.86 g, 8.33 mmol)in dichloromethane (20 ml) was treated with 4M HCl in dioxane (20 ml)for 2 h. Ether (200 ml) was added and the suspension was filtered,washed with ether (2×50 ml), hexane (50 ml) and pumped dry to givemethyl 4-(2-aminoethylsulfonyl)benzoate hydrochloride (2.23 g) which wascoupled with benzofuran 2-carboxylic acid as described above to affordthe title compound. MS (M+1):388.

Proceeding as described in Example 1-3 above but using appropriatecommercially available starting materials the following compounds ofTable I-IV were prepared.

Table 1:

Cpd. 1

¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (t, J=5.8 Hz, 1H), 7.83 (d, J=7.5 Hz,2H), 7.69 (d, J=9.1 Hz, 2H), 7.46 (m, 3H), 6.99 (d, J=9.1 Hz, 2H), 4.16(t, J=5.8 Hz, 2H), 3.63 (q, J=5.8 Hz, 2H). EM (calc.): 300.1; MS (ESI)m/e: 301.1 (M−1)⁺, 299.0 (M+1)⁻.

Cpd. 2

¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.92 (s, 1H), 8.41 (t, J=6Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.58 (d, J=6.8 Hz, 2H), 7.46 (d, J=15.6Hz, 1H), 7.45-7.37 (m, 3H), 7.03 (d, J=8.8 Hz, 2H), 6.72 (d, J=15.6 Hz,1H), 4.13 (t, J=5.2 Hz, 2H), 3.60 (q, J=5.6 Hz, 2H). EM (calc.): 326.1;MS (ESI) m/e (M+1H)⁺: 327.1, (M−1H)⁻: 325.2.

Cpd. 3

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.42 (t, J=4.8Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.27 (t, J=7.2 Hz, 2.0 Hz), 7.18 (t,J=7.2 Hz, 1H), 7.13 (d, J=7.2 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.07 (t,J=5.6 Hz, 2H), 3.49 (dq, J₁=5.6 Hz, J₂=1.6 Hz, 2H), 2.28 (ddd, J₁=4.0Hz, J₂=5.6 Hz, J₃=9.6 Hz, 1H), 1.95 (ddd, J₁=4.1 Hz, J₂=5.2 Hz, J₃=8.4Hz, 1H), 1.39 (ddd, J₁=4.0 Hz, J₂=5.2 Hz, J₃=9.2 Hz, 1H), 1.24 (ddd,J₁=4.0 Hz, J₂=6.4 Hz, J₃=10.4 Hz, 1H). EM (calc.): 340.1; MS (ESI) m/e(M+1H)⁺: 341.2, (M−1H)⁻: 339.2.

Cpd. 4

¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.92 (s, 1H), 8.31 (t, J=5.6Hz, 1H), 7.73 (d, J=9.2 Hz, 2H), 7.52 (d, J=9.2 Hz, 2H), 7.41 (d, J=15.6Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.55 (d, J=15.6Hz, 1H), 4.12 (t, J=5.6 Hz, 2H), 3.81 (s, 3H), 3.58 (q, J=5.6 Hz, 2H).EM (calc.): 356.1; MS (ESI) m/e (M+1H)⁺: 357.2, (M−1H)⁻: 355.2.

Cpd. 5

¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.80 (s, 1H), 8.01 (t, J=4.8Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.14-7.02 (m, 5H), 6.86 (d, J=8.8 Hz,2H), 3.32 (q, J=5.6 Hz, 2H), 2.71 (t, J=7.2, 2H), 2.30 (t, J=7.6 Hz,2H). EM (calc.): 328.1; MS (ESI) m/e (M+1H)⁺: 329.2, (M−1H)⁺: 327.0.

Cpd. 6

¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 10.89 (s, 1H), 8.95 (br s,1H), 8.22 (t, J=5.6 Hz, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.0 Hz,1H), 7.37 (d, J=8.4 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.08 (t, J=7.6 Hz,1H), 7.02 (d, J=8.4 Hz, 2H), 6.93 (t, J=8.4 Hz, 1H), 4.09 (pseudo t,J=6.0 Hz, 2H), 3.58 (s, 2H), 3.50 (pseudo q, J=5.6 Hz, 2H). EM (calc.):353.1; MS (ESI) m/e (M+1H)⁺: 353.9, (M−1H)⁻: 252.0.

Cpd. 7

¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.80 (t, J=5.6 Hz, 1H), 7.82(d, J=7.6 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.19(t, J₁=5.2 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 4.21 (pseudo t, J=6.0 Hz,2H), 3.67 (pseudo q, J=5.6 Hz, 2H). EM (calc.): 306.1; MS (ESI) m/e(M+1H)⁺: 307.0, (M−1H)⁻: 304.9.

Cpd. 8

¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.9 (t, J=5.4 Hz, 1H), 8.67(d, J=4.6 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.9 Hz, 2H), 7.48(m, 1H), 6.99 (d, J=8.9 Hz, 2H), 4.17 (t, J=5.4 Hz, 2H), 3.65 (m, 2H).EM (calc.): 301.11; MS (ESI) m/e (M−1H)⁻: 300.0.

Cpd. 9

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (1H, s), 8.87 (1H, bs), 8.74 (1H, t,J=5.6 Hz), 7.93 (2H, d, J=8.0 Hz), 7.75 (2H, d, J=8.0 Hz), 7.69 (3H, m),7.47 (1H, t, J=8.0 Hz), 7.39 (2H, m), 6.99 (2H, d, J=8.9 Hz), 4.18 (2H,t, J=5.6 Hz), 3.66 (2H, m). EM (calc.): 376.41; MS (ESI) m/e (M+1H)⁺:377.1, (M−1H)⁻: 375.0.

Cpd. 10

EM (calc.): 376.1; MS (ESI) m/e (M+1)⁺: 376.9, (M−1)⁻: 375.1.

Cpd. 11

¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H0, 8.95 (s, 1H), 8.84 (t, J=6.0Hz, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.77 (d, J=9.2 Hz, 2H), 7.75 (d, J=7.2Hz, 2H), 7.59 (d, J=4.0 Hz, 1H), 7.49 (pseudo t, J=7.2 Hz, 2H), 7.41(pseudo t, J=7.6 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 4.22 (pseudo t, J=5.6Hz, 2H), 3.69 (pseudo q, J=5.2 Hz, 2H). EM (calc.): 382.1; MS (ESI) m/e(M+1H)⁺: 383.1, (M−1H)⁻: 381.0.

Cpd. 12

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.15 (s, 1H), 8.36 (t, J=5.6Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.32 (m, 1H), 6.97 (d, J=8.8 Hz, 2H),6.92 (m, 1H), 6.88 (m, 1H), 4.04 (t, J=5.6 Hz, 2H), 3.66 (s, 2H), 3.45(m, 2H). EM (calc.): 320.1; MS (ESI) m/e (M+1H)⁺: 320.9, (M−1H)⁻: 319.0.

Cpd. 13

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.87 (m, 2H), 8.45 (s, 1H),7.97 (m, 4H), 7.71 (d, J=8.8 Hz, 2H), 7.59 (m, 2H), 7.02 (d, J=8.8 Hz,2H), 4.21 (t, J=5.6 Hz, 2H), 3.71 (m, 2H). EM (calc.): 350.1; MS (ESI)m/e (M+1H)⁺: 350.9, (M−1H)⁻: 349.1.

Cpd. 14

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.98 (m, 2H), 8.52 (m, 2H),8.19 (d, J=8.8 Hz, 1), 8.08 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H),7.62 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 4.22 (t, J=5.6 Hz, 2H), 3.72 (m,2H). EM (calc.): 351.1; MS (ESI) m/e (M+1H)⁺: 351.8, (M−1H)⁻: 349.9.

Cpd. 15

EM (calc.): 383.1; MS (ESI) m/e (M+1)⁺: 383.9, (M−1)⁻: 382.2.

Cpd. 16

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.88 (s, 1H), 8.61 (t, J=4.8Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.8Hz, 2H), 6.99 (d, J=8.6 Hz, 2H), 4.15 (t, J=5.6 Hz, 2H), 3.62 (m, 2H),1.29 (s, 9H). EM (calc.): 356.2; MS (ESI) m/e (M+1H)⁺: 357.0, (M−1H)⁻:355.1.

Cpd. 17

¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.95 (s, 1H), 8.72 (d, J=5.2Hz, 1H), 8.56 (t, J=4.8 Hz, 1H), 8.40 (d, J=7.6 Hz, 1H), 7.80 (m, 1H),7.71 (d, J=8.8 Hz, 2H), 7.55 (d, J=16.0 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H),6.90 (d, J=16.0 Hz, 1H), 4.12 (t, J=5.6 Hz, 2H), 3.59 (m, 2H). EM(calc.): 327.1; MS (ESI) m/e (M+1H)⁺: 328.1, (M−1H)⁻: 326.1.

Cpd. 18

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.88 (s, 1H), 8.73 (t, J=5.6Hz, 1H), 7.93 (d, J=9.2 Hz, 2H), 7.69 (m, 4H), 7.47 (t, J=2.4 Hz, 2H),7.01 (d, J=9.2 Hz, 2H), 6.29 (t, J=2.4 Hz, 2H), 4.18 (t, J=5.6 Hz, 2H),3.66 (m, 2H). EM (calc.): 365.1; MS (ESI) m/e (M+1H)⁺: 366.0, (M−1H)⁻:364.2.

Cpd. 19

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.53 (t, J=5.6 Hz, 1H), 7.80(d, J=9.2 Hz, 2H), 7.70 (d, J=9.2 Hz, 2H), 6.99 (m, 4H), 5.95 (m, 1H),5.80 (m, 1H), 4.96 (s, 1H), 4.14 (t, J=5.6 Hz, 2H), 3.60 (m, 2H), 2.00(m, 3H), 1.72 (m, 3H). EM (calc.): 396.2; MS (ESI) m/e (M+1H)⁺: 397.1,(M−1H)⁻: 395.2.

Cpd. 20

¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 9.35 (t, J=5.6 Hz, 1H), 8.25(d, J=7.6 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H),7.68-7.58 (m, 2H), 7.03 (d, J=9.2 Hz, 2H), 4.23 (pseudo t, J=6.4 Hz,2H), 3.74 (pseudo q, J=6.0 Hz, 2H). EM (calc.): 357.1; MS (ESI) m/e(M+1H)⁺: 358.1, (M−1H)⁻: 356.0.

Cpd. 21

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 9.47 (t, J=5.6 Ha, 1H), 7.90(pseudo t, J=9.2 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 4.59 (td, J₁=7.6 Hz,J₂=0.8 Hz, 1H), 7.52 (td, J₁=8.0 Hz, J₂=1.2 Hz, 1H), 7.03 (d, J=8.8 Hz,2H), 4.24 (t, J=6.0 Hz, 2H), 3.72 (pseudo q, J=6.0 Hz, 2H). EM (calc.):341.1; MS (ESI) m/e (M+1H)⁺: 342.1, (M−1H)⁻: 340.2.

Cpd. 22

¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 9.70 (s, 1H), 8.91, (t, J=5.6Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 4.10 (m, 2H),3.93 (m, 2H), 3.54 (m, 2H), 3.27 (m, 2H), 3.08 (m, 2H), 2.21 (m, 1H),2.01 (m, 1H), 1.51 (m, 10H). EM (calc.): 375.2; MS (ESI) m/e (M+1H)⁺:376.1, (M−1H)⁻: 374.1.

Cpd. 23

¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.35 (d, J=6.8 Hz, 2H), 7.72(d, J=9.2 Hz, 2H), 7.25 (d, J=6.8 Hz, 2H), 6.98 (d, J=9.2 Hz, 2H), 4.10(t, J=5.6 Hz, 2H), 3.97 (m, 2H), 3.54 (m, 10H). EM (calc.): 399.2; MS(ESI) m/e (M+1H)⁺: 400.1, (M−1H)⁻: 398.1.

Cpd. 24

EM (calc.): 290.1; MS (ESI) m/e (M+1)⁺: 291.1, (M−1)⁻: 289.2.

Cpd. 25

EM (calc.): 377.1; MS (ESI) m/e (M+1)⁺: 377.9, (M−1)⁻: 376.0.

Cpd. 26

EM (calc.): 377.1; MS (ESI) m/e (M+1)⁺: 378.0, (M−1)⁻: 375.9.

Cpd. 27

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.11 (t, J=5.6 Hz, 1H), 7.70(d, J=9.2 Hz, 2H), 7.62 (m, 2H), 7.29 (m, 2H), 7.01 (d, J=9.2 Hz, 2H),4.21 (t, J=5.6 Hz, 2H), 3.71 (m, 2H). EM (calc.): 340.1; MS (ESI) m/e(M+1)⁺: 341.0, (M−1H)⁻: 339.1.

Cpd. 28

EM (calc.): 289.1; MS (ESI) m/e (M+1)⁺: 290.0, (M−1)⁻: 287.8.

Cpd. 29

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s 1H), 10.43 (s, 1H), 8.62 (t, J=6.0Hz, 1H), 7.94 (d, J=6.4 Hz, 2H), 7.853 (m, 4H), 7.70 (d, J=9.2 Hz, 2H),7.60 (m, 1H), 7.52 (m, 2H), 7.00 (d, J=9.2 Hz, 2H), 4.16 (t, J=6.0 Hz,2H), 3.63 (dt, J₁=5.6 Hz, J₂=6.0 Hz, 2H). EM (calc.): 419.2; MS (ESI)m/e (M+1)⁺: 420.2, (M−1)⁻: 418.3.

Cpd. 30

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.23 (t, J=6.0 Hz, 1H), 9.01(s, 1H), 8.89 (d, J=6.8 Hz, 2H), 8.38 (d, J=6.4 Hz, 2H), 7.70 (d, J=9.2Hz, 2H), 7.00 (d, J=9.2 Hz, 2H), 4.22 (t, J=5.6 Hz, 2H), 3.71 (m, 2H).EM (calc.): 384.1; MS (ESI) m/e (M+1H)⁺: 384.9, (M−1H)⁻: 382.9.

Cpd. 31

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.56(t, J=5.6 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.01 (t, J=5.6 Hz, 2H), 3.40(m, 2H), 1.95 (m, 3H), 1.69 (m, 12H). EM (calc.): 358.2; MS (ESI) m/e(M+1H)⁺: 358.9, (M−1H)⁻: 357.2.

Cpd. 32

EM (calc.): 336.09; MS (ESI) m/e (M−1H)⁻: 335.3.

Cpd. 33

EM (calc.): 370.12; MS (ESI) m/e (M−1H)⁻: 369.0.

Cpd. 34

EM (calc.): 344.10; MS (ESI) m/e (M+1H)⁺: 345.0, (M−1H)⁻: 343.1.

Cpd. 35

EM (calc.): 360.13; MS (ESI) m/e (M−1H)⁻: 359.1.

Cpd. 36

EM (calc.): 344.10; MS (ESI) m/e (M−1H)⁻: 358.8.

Cpd. 37

EM (calc.): 336.09; MS (ESI) m/e (M+1H)⁺: 337.2, (M−1H)⁻: 335.0.

Cpd. 38

EM (calc.): 328.14; MS (ESI) m/e (M+1H)⁺: 329.2, (M−1H)⁻: 327.2.

Cpd. 39

EM (calc.): 368.03; MS (ESI) m/e (M−1H)⁻: 367.0.

Cpd. 40

EM (calc.): 328.14; MS (ESI) m/e (M+1H)⁺: 328.8, (M−1H)⁻: 327.2.

Cpd. 41

EM (calc.): 364.08; MS (ESI) m/e (M+1H)⁺: 365.1, (M−1H)⁻: 363.2.

Cpd. 42

EM (calc.): 344.14; MS (ESI) m/e (M+1H)⁺: 345.1, (M−1H)⁻: 343.1.

Cpd. 43

EM (calc.): 344.14; MS (ESI) m/e (M+1H)⁺: 345.0, (M−1H)⁻: 343.2.

Cpd. 44

EM (calc.): 348.11; MS (ESI) m/e (M+1H)⁺: 348.8, (M−1H)⁻: 346.9.

Cpd. 45

EM (calc.): 412.11; MS (ESI) m/e (M+1H)⁺: 413.3, (M−1H)⁻: 411.0.

Cpd. 46

EM (calc.): 412.11; MS (ESI) m/e (M+1H)⁺: 413.2, (M−1H)⁻: 411.1.

Cpd. 47

EM (calc.): 376.14; MS (ESI) m/e (M+1H)⁺: 377.0, (M−1H)⁻: 375.2.

Cpd. 48

EM (calc.): 339.12; MS (ESI) m/e (M+1H)⁺: 340.1, (M−1H)⁻: 338.3.

Cpd. 49

¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 11.04 (s, 1H), 8.12 (d, J=7.6Hz, 2H), 8.01 (s, 1H), 7.70 (d, J=9.2 Hz, 2H), 7.40 (d, J=8.0, Hz, 1H),7.10 (m, 2H), 7.017 (d, J=8.8 Hz, 2H), 4.16 (t, J=5.6 Hz, 2H), 3.64 (m,2H). EM (calc.): 339.1; MS (ESI) m/e (M+1H)⁺: 340.0, (M−1H)⁻: 338.1.

Cpd. 50

¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 9.21 (t, J=5.2 Hz, 1H), 9.02(s, 1H), 8.15 (t, J=9.2 Hz, 2H), 7.94 (m, 1H), 7.74 (m, 3H), 7.02 (d,J=8.8 Hz, 2H), 4.24 (t, J=5.6 Hz, 2H), 3.75 (m, 2H). EM (calc.): 351.1;MS (ESI) m/e (M+1H)⁺: 352.0, (M−1H)⁻: 349.9.

Cpd. 51

¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H) 9.09 (d, J=4.4 Hz, 1H), 8.70(d, J=7.6 Hz, 1H), 8.65 (d, J=7.6 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.79(m, 4H), 7.10 (d, J=8.8 Hz, 2H), 4.30 (t, J=5.6 Hz, 2H), 3.89 (m, 2H).EM (calc.): 351.1; MS (ESI) m/e (M+1H)⁺: 352.0, (M−1H)⁻: 349.9.

Cpd. 52

¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (s, 1H), 11.04 (s, 1H), 8.88 (s, 1H),8.53 (t, J=5.6 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H),7.60 (d, J=8.4 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H),7.01 (d, J=8.8 Hz, 2H), 4.19 (t, J=6.0 Hz, 2H), 3.68 (m, 2H). EM(calc.): 340.1; MS (ESI) m/e (M+1)⁺: 341.1, (M−1H)⁻: 339.2.

Cpd. 53

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.89 (m, 2H), 8.45 (s, 1H),7.93 (s, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.20 (t,J=5.6 Hz, 2H), 3.69 (m, 2H). EM (calc.): 341.1; MS (ESI) m/e (M+1H)⁺:341.8, (M−1H)⁻: 340.0.

Cpd. 54

¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (s, 1H), 9.24 (d, J=8.0 Hz, 1H), 8.53(m 1H), 8.03 (m, 2H), 7.82 (t, J=6.8 Hz, 1H), 7.71 (m, 3H), 7.03 (d,J=8.4 Hz, 2H), 4.24 (t, J=4.8 Hz, 2H), 3.76 (m, 2H). EM (calc.): 351.1;MS (ESI) m/e (M+1H)⁺: 351.9, (M−1H)⁻: 350.1.

Cpd. 55

¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (s, 1H), 9.11 (s, 1H), 8.59 (s, 1H),8.25 (m, 1H), 7.87 (m, 2H), 7.70 (m, 2H), 7.02 (m, 2H), 4.23 (s, 2H),3.76 (s, 2H). EM (calc.): 351.1; MS (ESI) m/e (M+1H)⁺: 351.8, (M−1H)⁻:349.9.

Cpd. 56

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.47 (m, 1H), 9.23 (m, 1H),8.19 (m, 2H), 7.98 (m, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.4 Hz,2H), 4.25 (t, J=5.2 Hz, 2H), 3.78 (m, 2H). EM (calc.): 352.1; MS (ESI)m/e (M+1H)⁺: 352.8, (M−1H)⁻: 350.9.

Cpd. 57

EM (calc.): 350.11; MS (ESI) m/e (M+1H)⁺: 351.1, (M−1H)⁻: 349.1.

Cpd. 58

EM (calc.): 351.12; MS (ESI) m/e (M+1H)⁺: 352.2, (M−1H)⁻: 350.0.

Cpd. 59

EM (calc.): 365.14; MS (ESI) m/e (M+1H)⁺: 366.0, (M−1H)⁻: 364.2.

Cpd. 60

EM (calc.): 368.12; MS (ESI) m/e (M+1H)⁺: 369.0, (M−1H)⁻: 367.1.

Cpd. 61

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.88 (s, 1H), 8.68 (t, J=5.6Hz, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.70 (d,J=8.4 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.18 (t,J=6.0 Hz, 2H), 3.66 (m, 2H). EM (calc.): 340.1; MS (ESI) m/e (M+1H)⁺:341.0, (M−1H)⁻: 339.2.

Cpd. 62

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.11 (m, 2H), 7.98 (s, 1H),7.70 (d, J=9.2 Hz, 2H), 7.47 (d, J=7.6 Hz, 1H), 7.20 (t, J=8.4 Hz, 1H),7.13 (t, J=6.8 Hz, 1H), 7.01 (d, J=9.2 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H),3.82 (s, 3H), 3.62 (m, 2H). EM (calc.): 353.1; MS (ESI) m/e (M+1H)⁺:354.0, (M−1H)⁻: 351.9.

Cpd. 63

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.14 (t, J=5.6 Hz, 1H), 8.19(d, J=8.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.85 (t, J=8.4 Hz, 1H), 7.69(m, 4H), 7.03 (d, J=8.8 Hz, 2H), 4.24 (t, J=6.0 Hz, 2H), 4.15 (s, 3H),3.78 (m, 2H). EM (calc.): 381.1; MS (ESI) m/e (M+1H)⁺: 381.9, (M−1H)⁻:380.1.

Cpd. 64

EM (calc.): 380.14; MS (ESI) m/e (M+1H)⁺: 381.0, (M−1H)⁻: 379.0.

Cpd. 65

EM (calc.): 380.14; MS (ESI) m/e (M+1H)⁺: 381.2, (M−1H)⁻: 378.9.

Cpd. 66

EM (calc.): 351.12; MS (ESI) m/e (M+1H)⁺: 352.0, (M−1H)⁻: 350.0.

Cpd. 67

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.26 (t, J=5.6 Hz, 1H), 7.70(d, J=8.8 Hz, 2H), 7.41-7.35 (m, 4H), 7.29 (m, 1H), 7.21 (s, 1H), 7.00(d, J=9.2, 2H), 4.12 (t, J=6.0 Hz, 2H), 3.54 (pseudo q, J=6.0 Hz, 2H),2.01 (s, 3H). EM (calc.): 340.1; MS (ESI) m/e (M+1H)⁺: 340.9, (M−1H)⁻:339.2.

Cpd. 68

¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 10.72 (br s, 1H), 8.81 (t,J=5.2 Hz, 1H), 7.94 (dd, J₁=8.4 Hz, J₂=2.0 Hz, 1H), 7.73 (d, J=8.8 Hz,2H), 7.32 (s, 1H), 7.03 (d, J=9.2 Hz, 2H), 4.60 (s, 2H), 4.13 (pseudo t,J=5.6 Hz, 2H), 3.70 (pseudo q, J=5.2 Hz, 2H), 2.83 (s, 6H). EM (calc.):397.2; MS (ESI) m/e (M+1H)⁺: 398.1, (M−1H)⁻: 396.0.

Cpd. 71

¹H NMR (DMSO-d₆): 0.92 (3H, t, 7 Hz); 1.53 (1H, m); 1.72 (1H, m); 2.48(3H, s); 3.94 (1H, m); 4.03 (2H, m); 6.62 (1H, s); 6.78 (1H, dd); 6.92(1H, d); 7.01 (2H, d); 7.08 (1H, s); 7.31 (1H, d); 7.7 (2H, d); 8.27(2H, d, 7 Hz); 9.25 (1H, s). MS (M+1): 425.

Cpd. 72

¹H NMR (DMSO-d₆): 0.90 (2H, dd); 0.91 (3H, t, 7 Hz); 1.1 (2H, br. S);1.52 (1H, m); 1.68 (1H, m); 1.92 (1H, m); 2.0-2.1 (3H, m*); 2.25 (1H,m); 2.48 (3H, s); 3.24 (1H, m); 3.37 (4H, m); 3.54 (1H, m); 3.95 (1H,m); 4.03 (2H, m); 6.66 (1H, s); 6.97 (1H, m); 6.99 (2H, d, 9 Hz); 7.07(1H, dd, 9.2 Hz); 7.12 (1H, d, 6 Hz): 7.28 (1H, dd, 20.2 Hz); 7.45 (1H,t, 9 Hz), 7.7 (2H, d, 9 Hz); 8.29 (1H, d, 8 Hz). MS (M+1): 548.

Cpd. 73

¹H NMR (DMSO-d₆): 2.00 (2H, m); 2.64 (1H, m); 2.75 (1H, m); 4.1 (1H, m);4.18 (1H, m); 4.39 (1H, m); 6.98 (2H, d, 9 Hz); 7.14 (1H, m); 7.19-7.28(5H, m); 7.32 (1H, t, 8 Hz); 7.45 (1H, m); 7.58 (1H, s); 7.65 (1H, d, 7Hz); 7.68 (2H, d, 9 Hz); 7.76 (1H, d, J=7 Hz) 8.74 (1H, d, 7 Hz). MS(M−1): 443.

Cpd. 78

1H NMR (DMSO-d₆): 3.56 (2H, m); 4.15 (1H, m); 4.23 (1H, m); 4.57 (2H,s); 4.94 (1H, m); 6.99 (2H, d, 9 Hz); 7.33 (1H, t, 7 Hz); 7.38 (5H, s);7.47 (1H, t, 7 Hz) 7.58 (1H, s); 7.65 (1H, d, 8 Hz); 7.70 (2H, d, 9 Hz);7.77 (1H, d, 8 Hz); 8.90 (1H, s); 9.0 (1H, d, 8 Hz). MS (M+1): 509.

Cpd. 79

¹H NMR (DMSO-d₆): 2.7-2.81 (2H, m); 3.78 (2H, s); 4.12 (1H, dd, 10.5Hz); 4.22 (1H, dd, 10.7 Hz); 4.51 (1H, m); 6.97 (2H, d, 9 Hz); 7.22 (1H,m); 7.28 (2H, m); 7.29 (2H, s); 7.33 (1H, t, 7 Hz); 7.46 (1H, td, 7.1Hz); 7.58 (1H, s); 7.65 (1H, d, 8 Hz); 7.70 (2H, d, 9 Hz); 7.77 (2H, d,8 Hz); 8.79 (1H, d, 8 Hz). MS (M+1): 475.

Cpd. 80

¹H NMR (DMSO-d₆): 2.47 (3H, d, 1 Hz); 3.57-3.62 (3H, m); 3.77 (3H, s);4.08 (1H, t, 6 Hz); 6.64 (1H, s); 6.92 (1H, dd, 9.3 Hz); 6.99 (2H, d, 9Hz); 7.12-7.15 (2H, s+d); 7.42 (1H, d, 9 Hz); 7.7 (2H, d, 9 Hz); 8.49(1H, t, 6 Hz); 8.88 (1H, s). MS (M+1): 411.

Cpd. 91

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.24 (t, J=5.6Hz, 1H), 7.73 (d, J=9.2 Hz, 2H), 7.57 (d, J=6.8 Hz, 2H), 7.44 (d, J=16.0Hz, 1H, buried under m at 7.41), 7.41 (m, 3H), 7.00 (d, J=8.8 Hz, 2H),6.63 (d, J=16.0 Hz, 1H), 4.10 (pseudo t, J=6.0 Hz, 2H), 3.37 (pseudo q,J=6.4 Hz, 2H), 1.96 (pseudo p, J=6.4 Hz, 2H). EM (calc.): 340.1; MS(ESI) m/e (M+1H)⁺: 341.2, (M−1H)⁻: 339.3.

Cpd. 92

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.15 (s, 1H), 7.73 (d, J=8.4Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.38 (d, J=15.6 Hz, 1H), 6.99 (m, 4H),6.48 (d, J=15.6 Hz, 1H), 4.09 (pseudo t, J=6.0 Hz, 2H), 3.80 (s, 3H),3.35 (pseudo q, J=5.2 Hz, 2H), 1.94 (pseudo q, J=6.0 Hz, 2H). EM(calc.): 370.2; MS (ESI) m/e (M+1H)⁺: 371.0, (M−1H)⁻: 368.9.

Cpd. 93

¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.90 (t, J=5.6 Hz, 1H), 8.31(s, 1H), 7.98 (dd, J₁=7.2 Hz, J₂=1.6 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H),7.40 (pseudo t, J=7.2 Hz, 2H), 7.31 (pseudo tt, J₁=7.2 Hz, J₂=2.0 Hz,1H), 6.90 (d, J=9.2 Hz, 2H), 4.03 (t, J=5.6 Hz, 2H), 3.42 (pseudo q,J=6.0 Hz, 2H), 1.98 (pseudo p, J=6.0 Hz, 2H). EM (calc.): 397.1; MS(ESI) m/e (M+1H)⁺: 397.9, (M−1H)⁻: 396.0.

Cpd. 94

¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.26 (d, J=7.2 Hz, 1H), 7.74(d, J=8.4 Hz, 2H), 7.58 (d, J=7.2 Hz, 2H), 7.44 (m, 4H), 7.05 (d, J=8.8Hz, 2H), 6.68 (d, J=16.4 Hz, 1H), 4.27 (m, 1H), 4.07 (m, 1H), 3.96 (m,1H), 1.25 (d, J=6.8 Hz, 3H). EM (calc.): 340.1; MS (ESI) m/e (M+1H)⁺:341.1, (M−1H)⁻: 339.1.

Cpd. 95

¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.74(d, J=8.8 Hz, 2H), 7.58 (d, J=7.2 Hz, 2H), 7.46 (d, J=16.0 Hz, 1H), 7.42(m, 3H), 7.04 (d, J=9.2 Hz, 2H), 6.68 (d, J=16.4 Hz, 1H), 4.27 (pseudop, J=6.8 Hz, 1H) 4.07 (dd, J₁=5.6 Hz, J₂=10.0 Hz, 1H), 3.96 (dd, J₁=5.6Hz, J₂=9.6 Hz, 1H), 1.25 (d, J=7.2 Hz, 3H). EM (calc.): 340.1; MS (ESI)m/e (M+1H)⁺: 341.1, (M−1H)⁻: 339.1.

Cpd. 96

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.87 (s, 1H), 8.12 (d J=8.0Hz, 1H), 7.67 (dt, J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.54 (dd, J₁=8.4 Hz,J₂=1.6 Hz, 2H), 7.43-7.33 (m, 4H), 6.99 (dt J₁=9.2 Hz, J₂=2 Hz, 2H),6.65 (d, J=15.6 Hz, 1H), 4.26 (m, 1H), 4.01 (dd, J₁=9.6 Hz, J₂=4.8 Hz,1H), 3.94 (dd J₁=9.6 Hz, J₂=5.6 Hz, 1H), 1.66 (m, 1H), 1.49 (m, 2H),0.91 (d J=6.8 Hz, 3H), 0.87 (d, J=6.4 Hz, 3H). EM (calc.): 382.2; MS(ESI) m/e (M+1H)⁺: 383.0, (M−1H)⁻: 381.1.

Cpd. 97

¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H), 8.81 (s, 1H), 8.05 (d, J=8.4Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.47 (d, J=6.8 Hz, 2H), 7.37-7.28 (m,4H), 6.92 (dt, J₁=8.4 Hz, J₂=1.6 Hz, 2H), 6.61 (d, J=16 Hz, 1H), 4.21(m, 1H), 3.94 (m, 1H), 3.86 (m, 1H), 1.69 (d. J=12.4 Hz, 1H), 1.59-1.52(m, 4H), 1.42 (t, J=7.2 Hz, 2H), 1.28 (m, 1H), 1.15-1.05 (m, 3H), 090(m, 1H), 0.77 (m, 1H). EM (calc.): 422.2; MS (ESI) m/e (M+1H)⁺: 423.2,(M−1H)⁻: 421.2.

Cpd. 98

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.88 (s, 1H), 8.09 (d, J=8.4Hz, 1H), 7.69 (dt, J₁=8.8 Hz, J₂=2.8 Hz, 2H), 7.432-7.32 (series m, 4H),6.99 (dt, J₁=9.2 Hz, J₂=2.4 Hz, 2H), 6.73 (d, J=15.6 Hz, 1H), 4.05 (s,3H), 1.98 (m, 1H), 0.95 (d, J=2.4 Hz, 3H), 0.93 (d, J=2.4 Hz, 3H). EM(calc.): 368.2; MS (ESI) m/e (M+1H)⁺: 368.7, (M−1H)⁻: 367.1.

Cpd. 99

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.32 (d, J=8 Hz, 1H), 7.69(d, J=9.2 Hz, 2H), 7.53 (m, 2H), 7.43-7.34 (m, 4H), 7.28-7.22 (m, 3H),7.18 (m, 2H), 6.99 (d, J=9.2 Hz, 2H), 6.63 (d, J=16 Hz, 1H), 4.38 (m,1H), 4.02 (d, J=6.4 Hz, 2H), 2.99 (m, 1H), 2.88 (m, 1H). Missing OH orNH. EM (calc.): 416.2; MS (ESI) m/e (M+1H)⁺: 417.3, (M−1H)⁻: 415.2.

Cpd. 100

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.78 (s, 1H, 8.32 (d, J=8 Hz,1H), 7.69 (d, J=8.8 Hz, 2H), 7.52 (dd, J₁=8.4 Hz, J₂=1.6 Hz, 2H),7.41-7.34 (m, 4H), 7.28-7.23 (m, 4H), 7.19-7.15 (m, 1H), 6.99 (d, J=9.2Hz, 2H), 6.63 (d, J=15.6 Hz, 1H), 4.38 (m, 1H), 4.01 (d, J=4.4 Hz, 2H),2.99 (dd, J₁=13.6 Hz, J₂=6 Hz, 1H), 2.88 (dd, J₁=14 Hz, J₂=8 Hz, 1H). EM(calc.): 416.2; MS (ESI) m/e (M+1H)⁺: 417.2, (M−1H)⁻: 415.2.

Cpd. 101

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.87 (s, 1H), 8.12 (d, J=8.0Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.53 (d, J=7.2 Hz, 2H), 7.43-7.33 (m,4H), 6.99 (d, J=9.2 Hz, 2H), 6.65 (d, J=15.6 Hz, 1H), 4.25 (m, 1H), 4.01(dd, J=9.6 Hz, 4.8 Hz, 1H), 3.94 (dd J₁=9.6 Hz, J₂=5.6 Hz, 1H), 1.66 (m,1H), 11.48 (m, 2H), 0.91 (d J=6.8 Hz, 3H), 0.87 (d, J=6.4 Hz, 3H). EM(calc.): 382.2; MS (ESI) m/e (M+1H)⁺: 383.2, (M−1)⁻: 381.2.

Cpd. 102

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.87 (s, 1H), 8.08 (d, J=8Hz, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.55 (d, J=1.2 Hz, 2H), 7.43-7.32 (m,4H), 6.99 (d, J=9.2 Hz, 2H), 6.73 (d, J=16 Hz, 1H), 4.05 (s, 3H), 1.98(m, 1H), 0.946 (d, J=2 Hz, 3H), 0.93 (d, J=2.4 Hz, 3H). EM (calc.):368.2; MS (ESI) m/e (M+1H)⁺: 369.1, (M−1H)⁻: 367.1.

Cpd. 103

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.69(dt, J₁=8.8 Hz, J₂=2.8 Hz, 2H), 7.54 (dd, J₁=6.8, J₂=1.2 Hz, 2H),7.43-7.32 (m, 4H), 6.99 (dt, J₁=8.8 Hz, J₂=3.2 Hz, 2H), 6.66 (d, J=15.6Hz, 1H), 4.16 (m, 1H), 4.03 (dd, J₁=10 Hz, J₂=5.6 Hz, 1H), 3.96 (dd,J₁=10 Hz, J₂=5.2 Hz, 1H), 1.67 (m, 1H), 1.53 (m, 1H), 1.36-1.27 (m, 4H),0.87 (t, J=6.4 Hz, 3H). Missing 1H, NH or OH. EM (calc.): 382.2; MS(ESI) m/e (M+1H)⁺: 383.1, (M−1H)⁻: 381.1.

Cpd. 104

¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.64(dt, J₁=8.8 Hz, J₂=2 Hz, 2H), 7.46 (dd, J₁=7.6 Hz, J₂=2 Hz, 2H),7.34-7.18 (series m, 6H), 6.93 (dt, J₁=9.2 Hz, J₂=2.8 Hz, 2H), 6.54 (d,J=15.6 Hz, 1H), 4.31 (m, 1H), 3.95 (d, J=4.8 Hz, 2H), 2.93 (dd, J₁=13.6Hz, J₂=5.6 Hz, 1H), 2.79 (dd, J₁=13.6 Hz, J₂=8.4 Hz, 1H). EM (calc.):450.1; MS (ESI) m/e (M+1)⁺: 451.2; (M−1)⁻: 449.2.

Cpd. 105

¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.07 (d, J=8 Hz, 1H), 7.62(dt, J₁=8.8 Hz, J₂=2.8 Hz, 2H), 7.47 (dd, J₁=8.8 Hz, J₂=1.6 Hz, 2H),7.34-7.26 (series m, 4H), 6.93 (dt, J₁=8.8 Hz, J₂=2.8 Hz, 2H), 6.61 (d,J=15.6 Hz, 1H), 4.04 (m, 1H), 3.98 (dd, J₁=15.6 Hz, J₂=5.6 Hz, 1H), 3.90(dd, J₁=9.2, J₂=5.6 Hz, 1H), 1.64 (m, 1H), 1.46 (m, 1H), 0.85 (t, J=6.8Hz, 3H). EM (calc.): 354.2; MS (ESI) m/e (M+1H)⁺: 354.6, (M−1H)⁻: 353.2.

Cpd. 106

¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.07 (d, J=8 Hz, 1H), 7.62 (dJ=8.8 Hz, 2H), 7.47 (dd, J₁=6.8 Hz, J₂=1.6 Hz, 2H), 7.35-7.62 (series m,4H), 6.93 (dt, J₁=9.2, J₂=2 Hz, 2H), 6.61 (d, J=15.6 Hz, 1H), 3.98 (dd,J₁=9.6 Hz, J₂=5.6 Hz, 1H), 3.90 (dd, J₁=9.6, J₂=4.8 Hz, 1H), 1.65 (m,1H), 1.49 (m, 1H), 0.85 (t, J=7.2 Hz, 3H). EM (calc.): 354.2; MS (ESI)m/e (M+1H)⁺: 354.8, (M−1)⁻: 353.1.

Cpd. 107

EM (calc.): 400.49; MS (ESI) m/e (M+1): 401.0, (M−1): 399.0.

Cpd. 108

EM (calc.): 400.49; MS (ESI) m/e (M+1): 401.1, (M−1): 399.2.

Cpd. 109

¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.80 (br s, 1H), 8.73 (d,J=8.4 Hz, 1H), 7.62 (d, J=9.2 Hz, 2H), 7.48 (d, J=6.8 Hz, 2H), 7.38-7.27(series m, 8H), 7.21 (t, J=7.2 Hz, 1H), 6.93 (d, J=8.8, 2H), 6.69 (d,J=15.6 Hz, 1H), 5.30 (dd, J₁=13.6 Hz, J₂=7.6 Hz, 1H), 4.19 (d, J=6.4 Hz,2H). EM (calc.): 402.2; MS (ESI) m/e (M+1)⁺: 403.2, (M−1H)⁻: 400.9.

Cpd. 110

¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.80 (br s, 1H), 8.74 (d, J=8Hz, 1H), 7.62 (dt, J₁=8.8 Hz, J₂=2 Hz, 2H), 7.48 (dd, J₁=6.4 Hz, J₂=1.6Hz, 2H), 7.39-7.27 (series m, 8H), 7.21 (tt, J₁=7.6 Hz, J₂=1.2 Hz, 1H),6.93 (dt, J₁=9.2 Hz, J₂=2.4 Hz, 2H), 6.69 (d, J=15.6, 11H), 5.29 (dd,J₁=8 Hz, J₂=6.4 Hz, 1H), 4.18 (d, J=6.4 Hz, 2H). EM (calc.): 402.2; MS(ESI) m/e (M+1H)⁺: 402.9, (M−1H)⁻: 401.2.

Cpd. 111

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=8 Hz, 1H), 7.83 (d, J=8.8 Hz,2H), 7.48 (d, J=6.4 Hz, 2H), 7.39-7.27 (series m, 4H), 7.01 (d, J=8.8Hz, 2H), 6.58 (d, J=16.4 Hz, 1H), 4.25 (m, 1H), 4.03 (m, 2H), 3.73 (s,3H), 3.12 (m, 2H), 2.06 (m, 1H), 1.93 (m, 1H). EM (calc.): 432.1; MS(ESI) m/e (M+1H)⁺: 433.2, (M−1)⁻: 430.0.

Cpd. 112

¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=8 Hz, 1H), 7.82 (d, J=8.8 Hz,2H), 7.48 (d, J=8.8 Hz, 2H), 7.84-7.29 (series m, 4H), 7.01 (d, J=8.8Hz, 2H), 6.58 (d, J=16.4 Hz, 1H), 4.35 (m, 1H), 4.03 (m, 2H), 3.70 (s,3H), 3.13 (m, 2H), 2.06 (m, 1H), 1.93 (m 1H). EM (calc.): 432.1; MS(ESI) m/e (M+1)⁺: 432.2, (M−1)⁻: 430.2.

Cpd. 113

¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J=8.0 Hz, 1H), 7.83 (dt, J₁=9.2 Hz,J₂=2.8 Hz, 2H), 7.48 (dd, J₁=6 Hz, J₂=1.6 Hz, 2H), 7.39 (d, J=16 Hz,1H), 7.31 (m, 9H), 6.97 (dt, J₁=9.2 Hz, J₂=2.4 Hz, 2H), 6.57 (d, J=16Hz, 1H), 4.72 (m, 1H), 4.50 (s, 1H), 4.16 (dd, J₁=9.6 Hz, J₂=5.2 Hz),1H, 4.08 (dd, J₁=10 Hz, J₂=4.8 Hz, 1H), 3.45 (dd, J₁=14.4 Hz, J₂=5.6 Hz,1H), 3.36 (dd, J₁=14.4 Hz, J₂=6.8 Hz, 1H). EM (calc.): 492.2; MS (ESI)m/e (M+1H)⁺: 494.3, (M−1H)⁻: 492.2.

Cpd. 114

¹H NMR (400 MHz, DMSO) δ 11.07 (br s, 1H), 8.38 (d, J=7.6 Hz, 2H), 7.84(dd, J₁=3.6 Hz, J₂=1.2 Hz, 1H), 7.77 (dd, J₁=4.8 Hz, J₂=1.2 Hz, 1H),7.72 (d, J=8.4 Hz, 2H), 7.16 (dd, J₁=3.6 Hz, J₂=5.2 Hz, 1H), 7.02 (d,J=8.4 Hz, 2H), 4.20 (m, 1H), 4.13 (dd, J₁=6.4 Hz, J₂=9.6 Hz, 1H), 4.04(dd, J=5.2 Hz, J₂=9.2 Hz, 2H) 1.77 (m 1H), 1.63 (m, 1H), 1.21 (d, J=6.4Hz, 1H), 0.96 (t, J=7.2 Hz, 3H). EM (calc.): 334.1; MS (EST) m/e(M+1H)⁺: 335.0, (M−1H)⁻: 333.0.

Cpd. 115

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 7.94(d, J=8.4 Hz, 2H), 7.72 (m, 6H), 7.48 (m, 2H), 7.39 (m, 1H), 7.00 (d,J=8.4 Hz, 2H), 4.24 (m, 1H), 4.06 (m, 2H), 1.74 (m, 2H), 0.95 (t, J=7.2Hz, 3H). EM (calc.): 404.2; MS (ESI) m/e (M+1H)⁺: 405.2, (M−1H)⁻: 403.2.

Cpd. 116

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.87 (s, 1H), 8.50 (d, J=8.4Hz, 1H), 8.44 (s, 1H), 7.97 (m, 41, 7.70 (d, J=8.8 Hz, 2H), 7.59 (m,2H), 7.02 (d, J=8.8 Hz, 2H), 4.29 (m, 1H), 4.14 (m, 2H), 1.68 (m, 2H),0.98 (t J=7.2 Hz, 3H). EM (calc.): 378.2; MS (ESI) m/e (M+1H)⁺: 378.9,(M−1H)⁻: 377.0.

Cpd. 117

¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.82 (s, 1H), 8.27 (d, J=8.4Hz, 1H), 7.64 (d, J=9.2 Hz, 2H), 7.48 (dd, J₁=6.4 Hz, J₂=1.6 Hz, 2H),7.38 (d, J=15.6 Hz, 1H), 7.36-7.27 (m, 3H), 7.23-7.19 (m, 4H), 7.14 (m,1H), 6.92 (d, J=8.8 Hz, 2H), 6.61 (d, J=15.6 Hz, 1H), 4.29 (m, 1H), 4.08(dd, J₁=9.6 Hz, J₂=5.6 Hz, 1H), 3.98 (dd, J₁=9.6 Hz, J₂=4.4 Hz, 1H),3.70 (d, J=2.4 Hz, 2H), 2.67 (dd, J₁=6.8 Hz, J₂=13.6 Hz, 1H), 2.58 (dd,J₁=13.2 Hz, J₂=7.2 Hz, 1H). EM (calc.): 460.2; MS (ESI) m/e (M−1)⁻:460.8.

Cpd. 118

¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 7.83(d, J=7.2 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.52-7.42 (m, 3H), 6.99 (d,J=9.2 Hz, 2H), 4.22 (m, 1H), 4.11 (dd, J₁=6.4 Hz, J₂=10.0 Hz, 1H), 4.01(dd, J₁=6.0 Hz, J₂=9.6 Hz, 1H), 1.73 (m 1H0, 1.62 (m, 1H), 0.93 (t,J=7.6 Hz, 3H). EM (calc.): 328.1; MS EST) nm/e (M+1H)⁺: 329.1. (M−1H)⁻:327.0.

Cpd. 119

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.69(d, J=8.8 Hz, 2H), 7.24 (m, 5H), 6.96 (d, J=9.2 Hz, 2H), 3.94 (m 3H),3.43 (s, 2H), 1.64 (m, 1H), 1.47 (m, 1H), 0.86 (t, 7.2 Hz, 3H). EM(calc.): 342.2; MS (ESI) m/e (M+1H): 343.0, (M−1H)⁻: 341.1.

Cpd. 120

1H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.69(d, J=8.4 Hz, 2H), 7.23-7.10 (m, 5H), 6.94 (d, J=9.2 Hz, 2H), 3.94 (m,2H), 3.84 (m, 1H), 2.81 (t, J=7.2 Hz, 2H), 2.40 (t, J=7.6 Hz, 2H), 1.61(ddd, J₁=4.4 Hz, J₂=7.6 Hz, J₃=18.4 Hz, 1H), 1.41 (m, 1H), 0.81 (t,J=6.8 Hz, 3H). EM (calc.): 356.2; MS (ESI) m/e (M+1H)⁺; 357.1, (M−1H)⁻:355.1.

Cpd. 121

EM (calc.): 356.38; MS (ESI) m/e (M+1): 357.0, (M−1): 355.1.

Cpd. 122

¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.65 (d, J=8.8 Hz, 1H), 8.33(s, 1H), 8.00 (d, J=7.2 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.39 (pseudo t,J=7.2 Hz, 2H), 7.30 (pseudo t, J=7.6 Hz, 1H), 6.93 (d, J=9.2 Hz, 2H),4.20 (m, 1H), 4.23 (dd partially buried under peak at 4.20, J₁=9.2 Hz,J₂=16.8 Hz, 1H), 4.05 (dd, J₁=10.0 Hz, J₂=4.8 Hz, 1H), 1.69 (m 1H), 1.62(m, 1H), 0.88 (t, J=7.2 Hz, 3H). EM (calc.): 411.1; MS (ESI) m/e(M−1H)⁻: 410.1.

Cpd. 123

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.03 (d, J=7.6 Hz, 1H, 7.69(d, J=8.8 Hz, 2H), 7.48 (d, J=9.2 Hz, 2H), 7.36 (d, J=15.6 Hz, 1H), 6.99(d, J=9.2 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.52 (d, J=15.6 Hz, 1H), 4.09(m, 1H), 4.04 (dd, J₁=5.2 Hz, J₂=9.6 Hz, 1H), 3.95 (dd, J₁=5.2 Hz,J₂=9.6 Hz, 1H), 3.77 (s, 3H), 1.71 (m, 1H), 1.52 (m, 1H), 0.91 (t, J=6.8Hz, 3H). EM (calc.): 384.2; MS (ESI) m/e (M+1)⁺: 385.0, (M−1H)⁻: 383.2.

Cpd. 124

¹H NMR (400 MHz, DMSO-d₆ δ 11.07 (s, 1H), 10.62 (br s, 1H), 8.43 (d,J=8.0 Hz, 1H), 8.28 (d, J=1.6 Hz, 1H), 7.94 (dd, J₁=8.4 Hz, J₂=2.0 Hz,1H), 7.23 (d, J=8.4 Hz, 2H), 7.32 (s, 1H), 7.03 (d, J=8.8 Hz, 2H), 4.60(s, 2H), 4.28 (m, 1H), 4.17 (dd, J₁=10.0 Hz, J₂=6.8 Hz, 1H), 4.08 (dd,J₁=10.4 Hz, J₂=6.0 Hz, 1H), 2.84 (s, 6H), 1.80 (m, 1H), 1.65 (m, 1H),0.98 (t, J=7.6 Hz, 3H). EM (calc.): 425.2; MS (ESI) m/e (M+1H)⁺: 426.2,(M−1H)⁻: 424.1.

Cpd. 125

¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.80 (s, 1H), 8.27 (t, J=5.2Hz, 1H), 7.62 (J=8.8 Hz, 2H), 7.46 (d, J=6.8 Hz, 2H), 7.36 (d, J=12.8Hz, 1H), 7.33-7.28 (m, 3H), 6.95 (d, J=8.4 Hz, 2H), 6.60 (d, J=12.8 Hz,1H), 4.53 (ddd, J=5.6 Hz, 1H), 3.40 (m, 1H), 3.29 (m, 1H, buried underwater peak), 1.19 (d, J=6.4 Hz, 3H). EM (calc.): 340.1.

Cpd. 126

¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.87 (s, 1H), 8.34 (t, J=5.6Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.43 (d, J=13.2Hz, 1H), 7.40-7.35 (m, 3H), 7.02 (d, J=8.8 Hz, 2H), 6.67 (d, J=16 Hz,1H), 4.60 (ddd, J₁=6.0 Hz, J₂=11.6 Hz, J₃=17.6 Hz, 1H), 3.47 (m, 1H),3.36 (m 1H, buried under water peak), 1.26 (d, J=6.0 Hz, 3H). EM(calc.): 340.1; MS (ESI) m/e (M+1H)⁺: 341.0, (M−1H)⁻: 339.2.

Cpd. 127

EM (calc.): 397.1; MS (ESI) m/e (M−1H)⁻: 396.1.

Cpd. 128

EM (calc.): 397.1; MS (ESI) m/e (M+1H)⁺: 398.2, (M−1H)⁻: 396.2.

Cpd. 129

¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.69 (t, J=5.6 Hz, 1H), 7.84(d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.63 (m, 4H), 7.40 (t, J=7.6Hz, 2H), 7.32 (m, 1H), 6.98 (d, J=12.0 Hz, 2H), 4.62 (ddd, J₁=6.0 Hz,J₂=12.0 Hz, J₃=18.0 Hz, 1H), 3.52 (ddd, J₁=6.4 Hz, J₂=13.6 Hz, J₃=19.6Hz, 1H), 3.31 (m, 1H, buried under water peak), 1.23 (d, J=6.0 Hz, 3H).EM (calc.): 390.2; MS (ESI) m/e (M+1H)⁺: 391.3, (M−1H)⁻: 389.0.

Cpd. 130

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.24 (t, J=5.2 Hz, 1H), 7.68(d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.37 (d, J=15.6 Hz, 1H), 7.02(d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.51 (d, J=15.6 Hz, 1H), 4.58(pseudo q, J=5.6 Hz, 1H), 3.77 (s, 3H), 3.46 (ddd, J₁=4.8 Hz, J₂=13.2Hz, J₃=19.2 Hz, 1H), 3.32 (ddd, J₁=5.2 Hz, J₂=10.8 Hz, J₃=13.2 Hz, 1H),1.25 (d, J=6.0 Hz, 3H). EM (calc.): 370.2; MS (ESI) m/e (M+1H)⁺: 371.0,(M−1H)⁻: 369.1.

Cpd. 131

¹HNMR (DMSO-d₆): 3.67 (q, 2H), 4.18 (t, 2H), 7.01 (d, 2H), 7.7 (d, 2H),7.98 (d, 2H), 8.12 (d, 2H), 8.17 (d, 2H), 8.55 (s, 1H), 8.79 (m, 3H),11.05 (s, 1H). LC\MS: (M+1)⁺¹ 461.2, (M−1)⁻¹ 459.0.

Cpd. 132

¹H NMR (400 MHz, DMSO-d₆) δ: 11.08 (s, 1H), 8.94 (m, 2H), 7.75 (m, 3H),7.47 (d, 1H, J=8.1 Hz), 7.16 (d, 1H, J=8.1 Hz), 7.04 (d, 2H, J=9.6 Hz),4.22 (t, 2H, J=5.5 Hz), 3.71 (t, 2H, J=5.5 Hz), 3.36 (s, 3H). EM(calc.): 388.08; MS (ESI) m/e (M+1H)⁺: 388.9, (M−1H)⁻: 387.1.

Cpd. 133

¹HNMR (DMSO-d₆): 2.85 (s, 3H), 3.4 (s, 8H), 3.65 (q, 2H), 4.17 (t, 2H),7.00 (d, 2H), 7.54 (s, 1H), 7.7 (d, 2H), 7.9 (dd, 4H), 8.74 (t, 1H), 8.9(s, 1H), 10.2 (s, 1H), 11.05 (s, 1H). LC\MS: (M+1)⁺¹ 482.0, (M−1)⁻¹480.2.

Cpd. 134

¹HNMR (DMSO-d₆): 3.66 (q, 2H), 4.18 (t, 2H), 7.01 (d, 2H), 7.69 (m, 4H),7.91 (d, 2H), 8.02 (d, 3H), 8.33 (dd, 2H), 8.75 (t, 1H), 9.16 (s, 1H),10.99 (s, 1H), 1.05 (s, 1H). LC\MS: (M+1)⁺¹ 476.1, (M−1)⁻¹ 474.2.

Cpd. 135

¹HNMR (DMSO-d₆): 2.85 (s, 3H), 3.01 (m, 4H), 3.51 (d, 2H), 3.60 (q, 2H),4.00 (d, 2H), 4.13 (t, 2H), 6.98 (dd, 4H), 7.74 (dd, 4H), 8.48 (t, 1H),9.97 (s, 1H), 11.05 (s, 1H). LC\MS: (M+1)⁺¹ 399.3, (M−1)⁻¹ 397.2.

Cpd. 136

¹HNMR (DMSO-d₆): 1.4 (m, 2H), 1.8 (m, 2H), 2.95 (m, 2H), 3.6 (m, 5H),4.12 (t, 2H), 4.69 (s, 1H), 6.91 (d, 2H), 6.99 (d, 2H), 7.7 (dd, 4H),8.36 (t, 1H), 8.87 (s, 1H), 11.03 (s, 1H). LC\MS: (M+1)⁺¹ 400.2, (M−1)⁻¹398.3.

Cpd. 138

¹H NMR (400 MHz, DMSO-d₆) δ: 9.02 (t, 2H, J=5.3 Hz), 7.77-7.72 (m, 3H),7.27 (m, 1H), 7.11 (m, 1H), 7.03 (d, 2H, J=8.8 Hz), 4.22 (t, 2H, J=5.3Hz), 3.70 (t, 2H, J=5.3 Hz), 2.51 (s, 3H). EM (calc.): 372; MS (ESI) m/e(M+1H)⁺: 373.0, (M−1H)⁻: 371.0.

Cpd. 139

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 10.04 (s, 1H), 9.02 (t, 1H,J=5.7 Hz), 7.74 (d, 1H, J=2.7 Hz), 7.70 (d, 2H, J=8.5 Hz), 7.32 (m, 1H),7.25 (m, 1H), 7.00 (d, 2H, J=8.5 Hz), 4.72 (s, 2H), 4.19 (t, 2H, J=5.7Hz), 3.67 (m, 2H), 3.59 (m, 2H), 3.48 (m, 2H), 3.24 (s, 3H). EM (calc.):446.15; MS (ESI) m/e (M+1H)⁺: 447.4, (M−1H)⁻: 445.3.

Cpd. 140

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (br s, 1H), 9.25 (t, 1H, J=5.9 Hz),8.07 (d, 1H, J=8.6 Hz), 7.96 (d, 1H, J=8.6 Hz), 7.70 (m, 3H), 7.39 (t,1H, J=7.6 Hz), 7.01 (d, 2H, J=9.1 Hz), 6.88 (br s, 1H), 4.21 (t, 2H,J=5.9 Hz), 3.70 (q, 2H, J=5.9 Hz). EM (calc.): 367; MS (ESI) m/e(M+1H)⁺: 368.0, (M−1H)⁻: 366.2.

Cpd. 141

1H NMR (400 MHz, DMSO-d₆) δ: 11.04 (br s, 1H), 9.04 (t, 1H, J=5.9 Hz),7.80 (d, 1H, J=2.6 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.40 (m, 2H), 7.28 (t,1H, J=8.1 Hz), 7.05-6.92 (m, 5H), 5.35 (s, 2H), 4.18 (t, 2H, J=5.9 Hz),3.66 (q, 2H, J=5.9 Hz). EM (calc.): 464; MS (ESI) m/e (M+1H)⁺: 465.3,(M−1H)⁻: 463.1.

Cpd. 143

¹HNMR (DMSO-d₆): 2.55 (t, 3H), 2.80 (s, 3H), 3.07 (d, 3H), 3.4 (d, 2H),3.65 (q, 2H), 4.02 (s, 2H), 4.17 (t, 2H), 6.99 (d, 2H), 7.69 (d, 2H),7.91 (d, 2H), 8.01 (d, 2H), 8.23 (s, 1H), 8.75 (t, 1H), 9.6 (s, 1H),11.05 (s, 1H). LC\MS: (M+1)⁺¹ 496.3, (M−1)⁻¹ 494.4

Cpd. 144

MS (ESI) m/e: (M+1H)⁺: 302.0, (M−1H)⁻: 300.2.

Cpd. 145

MS (ESI) m/e: (M+1H)⁺: 318.1, (M−1H)⁻: 316.1.

Cpd. 146

MS (ESI) m/e: (M+1H)⁺: 318.1, (M−1H)⁻: 316.2.

Cpd. 147

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.28 (m, 2H), 8.15 (m, 1H),7.94 (m, 2H), 7.66 (m, 2H), 7.41 (m, 3H), 6.89 (m, 2H), 4.10 (m, 2H),3.63 (m, 2H). MS (ESI) m/e: (M+1H)⁺: 439.2, (M−1H)⁻: 437.2.

Cpd. 148

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.10 (t, J=8.0 Hz, 1H), 8.18(d, J=8.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.67(m, 4H), 7.04 (d, J=8.0 Hz, 2H), 4.45 (m, 2H), 4.23 (t, J=8.0 Hz, 2H),3.84 (m, 2H), 3.76 (m, 2H). MS (ESI) m/e: (M+1H)⁺: 426.3, (M−1H)⁻:424.2.

Cpd. 149

¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 10.31 (s, 1H), 9.10 (t, J=8.0Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.86 (t, J=8.0Hz, 1H), 7.69 (m, 4H), 7.02 (d, J=8.0 Hz, 2H), 4.74 (m, 2H), 4.23 (t,J=8.0 Hz, 2H), 3.77 (m, 2H), 3.70 (m, 2H). MS (ESI) m/e: (M+1H)⁺: 439.3,(M−1H)⁻: 437.3.

Cpd. 150

MS (ESI) m/e: (M+1H)⁺: 379.9, (M−1H)⁻: 379.9.

Cpd. 151

MS (ESI) m/e: (M+1H)⁺: 379.9, (M−1H)⁻: 379.9.

Cpd. 152

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (br s, 1H), 8.85 (d, 1H, J=9.0 Hz),8.20 (d, 1H, J=1.2 Hz), 8.18 (d, 1H, J=1.2 Hz), 7.85 (m, 1H), 7.70-7.65(m, 4H), 7.01 (t, 2H, J=8.7 Hz), 4.32 (m, 1H), 4.25 (m, 1H), 4.15 (s,3H), 4.13 (m, 1H), 1.77 (m, 2H), 0.95 (t, 3H, J=7.0). EM (calc.): 409;MS (ESI) m/e (M+1H)⁺: 410.2, (M−1H)⁻: 408.2.

Cpd. 153

¹H NMR (400 MHz, DMSO-d₆) δ: 11.05 (s, 1H), 10.17 (s, 1H), 8.65 (m, 1H),8.14 (m, 1H, 7.95 (m, 1H), 7.88 (d, 1H, J=8.2 Hz), 7.73-7.66 (m, 3H),7.62-7.59 (m, 2H), 7.05 (m, 2H), 4.24 (m, 2H), 3.89 (s, 3H), 3.73 (m,2H). EM (calc.): 380; MS (ESI) m/e (M+1H)⁺: 381.0, (M−1H)⁻: 379.1.

Cpd. 154

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 9.14 (t, 1H, J=6.0 Hz), 8.18(d, 1H, J=7.7 Hz), 8.07 (d, 1H, J=8.2 Hz), 7.85 (t, 1H, J=7.7 Hz),7.72-7.64 (m, 4H), 7.08 (d, 2H, J=9.1 Hz), 4.78 (m, 1H), 4.14 (s, 3H),3.66 (m, 1H), 3.55 (m, 1H), 1.31 (d, 3H, J=6.1 Hz). EM (calc.): 395; MS(ESI) m/e (M+1H)⁺: 396.1, (M−1H)⁻: 394.2.

Cpd. 155

MS (ESI) m/e: (M+1H)⁺: 377.9, (M−1H)⁻: 376.1.

Cpd. 156

MS (ESI) m/e: (M+1H)⁺: 408.3, (M−1H)⁻: 406.2.

Cpd. 157

MS (ESI) m/e: (M+1H)⁺: 373.9, (M−1H)⁻: 372.1.

Cpd. 158

MS (ESI) m/e: (M+1H)⁺: 422.3, (M−1H)⁻: 420.3.

Cpd. 159

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 9.10 (t, 1H, J=5.9 Hz), 8.16(d, 1H, J=8.4 Hz), 8.07 (d, 1H, J=8.4 Hz), 7.85 (t, 1H, J=7.9 Hz),7.71-7.65 (m, 4H), 7.03 (d, 2H, J=8.9 Hz), 4.60 (t, 2H, J=5.9 Hz), 4.23(t, 2H, J=5.1 Hz), 3.75 (q, 2H, J=5.9 Hz), 3.00 (m, 2H). EM (calc.):463; MS (ESI) m/e (M+1H)⁺: 464.3, (M−1H)⁻: 462.2.

Cpd. 160

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 8.78 (d, 1H, J=9.0 Hz), 8.15(d, 1H, J=8.3 Hz), 8.09 (d, 1H, J=8.5 Hz), 7.85 (t, 1H, J=6.7 Hz), 7.68(m, 4H), 7.00 (d, 2H, J=9.0 Hz), 4.61 (t, 2H, J=5.9 Hz), 4.32 (m, 1H),4.24 (m, 1H), 4.14 (m, 1H), 3.00 (m, 2H), 1.76 (m, 2H), 0.95 (t, 3H,J=7.0 Hz). EM (calc.): 491; MS (ESI) m/e (M+1H)⁺: 492.1, (M−1H)⁻: 490.1.

Cpd. 161

¹H NMR (400 MHz, DMSO-d₆) δ: 9.13 (t, 1H, J=6.1 Hz), 8.15 (d, 1H, J=8.1Hz), 8.07 (d, 1H, J=8.3 Hz), 7.86 (t, 1H, J=6.7 Hz), 7.71-7.67 (m, 4H),7.08 (d, 2H), J=8.7 Hz), 4.78 (m, 1H), 4.61 (t, 1H, J=5.5 Hz), 3.65 (m,1H), 3.55 (m, 1H), 3.00 (m, 2H), 1.31 (d, 3H, J=6.0 Hz). EM (calc.):477; MS (ESI) m/e (M+1H)⁺: 477.9, (M−1H)⁻: 476.1,

Cpd. 162

¹HNMR (DMSO-d₆): 3.56 (s, 2H), 4.09 (t, 2H), 6.57 (d, 1H), 6.77 (d, 1H),6.95 (m, 3H), 7.18 (t, 1H), 7.32 (d, 2H), 7.69 (d, 2H), 8.38 (t, 1H),9.6 (s, 1H), 11.05 (s, 1H). LC\MS: (M+1H)⁺¹ 343.2, (M−1)⁻¹ 341.3.

Cpd. 163

¹HNMR (DMSO-d₆): 3.55 (s, 2H), 4.08 (t, 2H), 6.4 (d, 1H), 6.8 (d, 2H),7.0 (d, 2H), 7.35 (d, 1H), 7.4 (d, 2H), 7.69 (d, 2H), 8.25 (t, 1H), 9.85(s, 1H), 11.05 (s, 1H). LC\MS: (M+1)⁺¹ 343.1, (M−1)⁻¹ 341.1.

Cpd. 164

EM (calc.): 420.17; MS (ESI) m/e (M+1H)⁺: 421.2, (M−1H)⁻: 419.5.

Cpd. 165

EM (calc.): 420.17; MS (ESI) m/e (M+1H)⁺: 421.3, (M−1H)⁻: 419.3.

Cpd. 166

EM (calc.): 420.17; MS (ESI) m/e (M+1H)⁺: 421.3, (M−1H)⁻: 419.3.

Cpd. 167

¹HNMR (DMSO-d₆): δ 8.89 (1H, s), 8.58 (1H, m), 7.71 (2H, m), 7.65 (1H,d), 7.56 (1H, d), 7.41 (1H, d), 7.36 (1H, t), 7.25 (1H, t), 7.21 (1H,s), 7.00 (2H, d), 6.74 (1H, dd), 4.11 (2H, t), 3.58 (2H, q).

Cpd. 168

EM (calc.): 420.17; MS (ESI) m/e (M+1H)⁺: 421.2, (M−1H)⁻: 419.3.

Cpd. 169

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 9.14 (s, 1H), 9.11 (t, J=8.0Hz, 1H), 8.93 (s, 1H), 8.63 (t, J=4.0 Hz, 1H), 8.17 (m, 1H), 7.72 (m,4H), 7.00 (d, J=8.0 Hz, 2H), 4.20 (t, J=8.0 Hz, 2H), 3.71 (m, 2H). MS(ESI) m/e: (M+1H)⁺: 384.1, (M−1H)⁻: 382.0.

Cpd. 170

MS (ESI) m/e: (M+1H)⁺: 451.0, (M−1H)⁻: 449.2.

Cpd. 171

MS (ESI) m/e: (M+1H)⁺: 409.3, (M−1H)⁻: 407.2.

Cpd. 172

¹HNMR (DMSO-d₆): 3.54 (q, 2H), 3.84 (s, 3H), 4.08 (t, 2H), 6.6 (d, 1H),6.98 (m, 4H), 7.35 (t, 1H), 7.5 (d, 1H), 7.65 (d, 1H), 7.69 (d, 2H),8.36 (t, 1H), 8.9 (s, 1H), 11.04 (s, 1H). LC\MS: (M⁺)⁺¹ 356.9, (M−1)⁻¹355.2.

Cpd. 173

¹HNMR (DMSO-d₆): 3.56 (q, 2H), 3.77 (s, 3H), 4.09 (t, 2H), 6.66 (d, 1H),6.93 (m, 2H), 6.99 (d, 2H), 7.1 (d, 2H), 7.29 (t, 1H), 7.39 (d, 1H),7.70 (d, 2H), 7.87 (d, 1H), 8.36 (t, 1H), 8.9 (s, 1H), 11.05 (s, 1H).LC\MS: (M+1)⁺¹ 357.1, (M−1)⁻¹ 355.1.

Cpd. 174

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.21 (t, J=8.0 Hz, 1H), 9.07(s, 1H), 8.92 (s, 1H), 8.67 (s, 1H), 7.70 (m, 4H), 7.01 (d, J=8.0 Hz,2H), 6.92 (m, 1H), 4.21 (t, J=8.0 Hz, 2H), 3.71 (m, 2H). MS (ESI) m/e:(M+1H)⁺: 421.2, (M−1H)⁻: 419.4.

Cpd. 175

¹HNMR (DMSO-d₆): δ 8.91 (1H, s), 8.44 (1H, t), 7.73 (2H, d), 7.72 (1H,s), 7.57 (1H, d), 7.44 (1H, d), 7.02 (2H, d), 6.50 (1H, d), 4.11 (2H,t), 3.58 (2H, q). LC/MS, M+1: 413.1.

Cpd. 176

¹HNMR (DMSO-d₆): 3.54 (q, 2H), 4.07 (t, 2H), 6.36 (d, 1H), 6.68 (s, 1H),6.98 (d, 2H), 7.32 (d, 1H), 7.69 (m, 3H), 7.98 (s, 1H), 8.27 (t, 1H),8.9 (s, 1H), 11.04 (s, 1H). LC\MS: (M+1)⁺¹ 316.9, (M−1)⁻¹ 315.3.

Cpd. 177

¹HNMR (DMSO-d₆): 3.55 (q, 2H), 4.08 (t, 2H), 6.47 (d, 1H), 6.98 (d, 2H),7.31 (d, 1H), 7.42 (d, 1H), 7.58 (m, 1H), 7.69 (d, 2H), 7.78 (s, 1H),8.30 (t, 1H), 8.9 (s, 1H), 11.04 (s, 1H). LC\MS: (M+1)⁺¹ 333.0, (M−1)⁻¹331.0.

Cpd. 178

¹HNMR (DMSO-d₆): δ 8.91 (1H, s), 8.40 (1H, t), 7.73 (2H, d), 7.61 (2H,m), 7.38 (1H, d), 7.11 (1H, dd), 7.01 (2H, d), 6.43 (1H, d), 4.11 (2H,t), 3.57 (2H, q). LC/MS, M+1: 333.0.

Cpd. 179

¹HNMR (DMSO-d₆): 2.31 (s, 3H), 3.55 (q, 2H), 4.09 (t, 2H), 6.6 (d, 1H),6.99 (d, 2H), 7.2-7.4 (m, 6H), 7.70 (d, 2H), 8.33 (t, 1H), 8.9 (s, 1H),11.04 (s, 1H). LC\MS: (M+1)⁺¹ 341.1, (M−1)⁻¹ 339.1.

Cpd. 180

¹HNMR (DMSO-d₆): 2.31 (s, 3H), 3.55 (q, 2H), 4.09 (t, 2H), 6.6 (d, 1H),6.99 (d, 2H), 7.2 (d, 2H), 7.38 (d, 1H), 7.42 (d, 2H), 7.69 (d, 2H),8.33 (t, 1H), 8.9 (s, 1H), 11.04 (s, 1H). LC\MS: (M+1)⁺¹ 341.2, (M−1)⁻¹339.2.

Cpd. 181

¹HNMR (DMSO-d₆): δ 8.87 (1H, s), 8.52 (1H, t), 7.70 (2H, d), 7.64 (1H,d), 7.52 (1H, d), 7.34 (1H, m), 7.24 (1H, t), 7.22 (1H, s), 6.99 (2H,d), 6.67 (1H, m), 4.09 (2H, t), 3.52 (2H, q), 2.48 (3H, m). LC/MS, M+1:381.0.

Cpd. 182

¹HNMR (DMSO-d₆): δ 8.88 (1H, s), 8.33 (1H, t), 7.68 (2H, d), 7.54 (1H,m), 7.41 (1H, d), 7.28 (1H, s), 7.24 (1H, m), 7.19 (1H, m), 6.95 (2H,d), 6.07 (1H, m), 4.11 (2H, t), 3.52 (2H, q), 2.15 (3H, m). LC/MS,M+1:381.1.

Cpd. 183

¹HNMR (DMSO-d₆): 2.94 (s, 6H), 3.54 (q, 2H), 4.07 (t, 2H), 6.38 (d, 1H),6.69 (d, 2H), 6.98 (d, 2H), 7.29 (d, 1H), 7.35 (d, 2H), 7.69 (d, 2H),8.15 (t, 1H), 8.87 (s, 1H), 11.04 (s, 1H). LC\MS: (M+1)⁺¹ 370.1, (M−1)⁻¹368.3.

Cpd. 184

¹HNMR (DMSO-d₆): 3.57 (q, 2H), 4.10 (t, 2H), 6.65 (d, 1H), 7.0 (d, 2H),7.14 (m, 2H), 7.42 (m, 1H), 7.6 (d, 1H), 7.72 (m, 3H), 7.87 (d, 1H),8.149 (t, 1H), 8.87 (s, 1H), 11.04 (s, 1H), 11.52 (s, 1H). LC\MS:(M+1)⁺¹ 366.2, (M−1)⁻¹ 364.4.

Cpd. 185

¹HNMR (DMSO-d₆): 2.36 (s, 3H), 3.56 (q, 2H), 4.10 (t, 2H), 6.56 (d, 1H),7.00 (d, 2H), 7.23 (m, 3H), 7.5 (d, 1H), 7.65 (d, 1H), 7.7 (d, 2H), 8.4(t, 1H), 8.87 (s, 1H), 11.04 (s, 1H). LC\MS: (M+1)⁺¹ 341.2, (M−1)⁻¹339.3.

Cpd. 186

¹HNMR (DMSO-d₆): 3.55 (q, 2H), 3.93 (s, 3H), 4.08 (t, 2H), 6.66 (d, 1H),6.79 (t, 1H), 6.86 (d, 1H), 6.98 (d, 2H), 7.15 (m, 1H), 7.4 (d, 1H),7.65 (d, 1H), 7.7 (d, 2H), 8.31 (t, 1H), 10.0 (s, 1H), 11.04 (s, 1H).LC\MS: (M+1)⁺¹ 343.1, (M−1)⁻¹ 340.9.

Cpd. 187

¹HNMR (DMSO-d₆): 3.57 (q, 2H), 3.93 (s, 3H), 4.09 (t, 2H), 6.75 (d, 1H),6.98 (m, 3H), 7.18 (m, 3H), 7.38 (d, 1H), 7.7 (d, 2H), 8.5 (t, 1H), 8.87(s, 1H), 11.04 (s, 1H). LC\MS: (M+1)⁺¹ 396.7, (M−1)⁻¹ 395.0.

Cpd. 188

¹HNMR (DMSO-d₆): 0.922 (t, 3H), 1.5-1.8 (m, 2H), 3.93 (s, 3H), 3.95-4.07(m, 3H), 6.8 (d, 1H), 6.98 (m, 3H), 7.19 (m, 3H), 7.36 (d, 1H), 7.69 (d,2H), 8.3 (d, 1H), 11.03 (s, 1H). LC\MS: (M+1)⁺¹ 425.2, (M−1)⁻¹ 423.2.

Cpd. 189

¹H NMR (DMSO-d₆): 0.95 (3H, t, 7 Hz); 1.53 (1H, m); 1.72 (1H, m); 2.52(3H, s); 3.79 (3H, s); 3.94 (1H, m); 4.06 (2H, m); 6.66 (1H, s); 6.93(1H, dd); 7.02 (2H, d); 7.15 (2H, m); 7.42 (1H, d); 7.7 (2H, d); 8.27(2H, d, 7 Hz); 8.87 (1H, d, 2 Hz). MS (M+1): 439.

Cpd. 190

¹HNMR (DMSO-d₆): 3.54 (q, 2H), 4.08 (t, 2H), 6.44 (d, 1H), 6.56 (s, 1H),6.75 (s, 1H), 6.98 (d, 2H), 7.23 (d, 1H), 7.70 (d, 2H), 7.75 (s, 1H),8.41 (t, 1H), 8.9 (s, 1H), 11.04 (s, 1H). LC\MS: (M+1)⁺¹ 317.0, (M−1)⁻¹315.2.

Cpd. 191

¹HNMR (DMSO-d₆): 3.5-4.05 (m, 14H), 4.18 (t, 2H), 6.99 (d, 2H), 7.69 (d,2H), 7.93 (d, 2H), 8.02 (d, 2H), 8.2 (s, 1H), 8.76 (t, 1H), 8.97 (s,1H), 11.05 (s, 1H). LC\MS: (M+1)⁺¹ 497.4, (M−1)⁻¹ 495.4.

Table 2:

Cpd. 1

EM (calc.): 370.2; MS (ESI) m/e (M+1)⁺: 371.1, (M−1)⁻: 369.2.

Cpd. 2

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.88 (s, 1H), 7.67 (d, J=9.2Hz, 2H), 7.51 (m, 3H), 7.36 (m, 8H), 6.92 (d, J=9.2 Hz, 2H), 6.27 (d,J=15.2 Hz, 1H), 4.16 (m, 4H). EM (calc.): 402.2; MS (ESI) m/e (M+1H)⁺:403.1, (M−1H)⁻: 401.1.

Cpd. 3

EM (calc.): 340.1; MS (ESI) m/e (M+1H)⁺: 341.0, (M−1H)⁻: 339.4.

Cpd. 4

EM (calc.): 398.13; MS (ESI) m/e (M+1H)⁺: 399.0, (M−1H)⁻: 397.1.

Cpd. 5

EM (calc.): 368.17; MS (ESI) m/e (M+1H)⁺: 368.8, (M−1H)⁻: 367.2.

Cpd 6

EM (calc.): 354.1; MS (ESI) m/e (M+1H)⁺: 354.8, (M−1H)⁻: 353.2.

Table 3:

Cpd. 1

¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 9.07 (t, J=5.2 Hz, 1H), 8.94(s, 1H), 8.16 (s, 1H), 8.07 (dd, J₁=2.4 Hz, J₂=8.4 Hz, 1H), 7.99 (dd,J₁=2.4 Hz, J₂=6.8 Hz, 1H), 7.77 (d, J=9.2 Hz, 2H), 7.50 (m. 2H), 7.08(d, J=8.8 Hz, 2H), 4.25 (pseudo t, J=5.6 Hz, 2H), 3.73 (pseudo q, J=5.2Hz, 2H). EM (calc.): 358.1; MS (ESI) m/e (M+1H)⁺: 357.0, (M−1H)⁻: 355.1.

Cpd. 2

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.92 (t, J=5.6 Hz, 1H), 8.88(s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.70 (d, J=9.2 Hz, 2H), 7.64 (d, J=8.0Hz, 1H), 7.55 (s, 1H), 7.46 (t, J=6.8 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H),7.01 (d, J=8.2 Hz, 2H), 4.18 (t, J=5.6 Hz, 2H), 3.67 (m, 2H). EM(calc.): 340.1; MS (ESI) m/e: (M+1H)⁺: 341.0, (M−1H)⁻: 339.1.

Cpd. 3

¹H NMR (400 MHz, DMSO-d₆): 11.57 (s, 1H), 11.04 (s, 1H), 8.71 (t, J=5.6Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.16 (t, J=8.4 Hz, 1H), 7.12 (m, 1H), 7.00 (m, 3H), 4.18 (t,J=5.6 Hz, 2H), 3.68 (m, 2H). EM (calc.): 339.1; MS (ESI) m/e (M+1H)⁺:340.1, (M−1H)⁻: 338.3.

Cpd. 4

EM (calc.): 353.1; MS (ESI) m/e (M+1)⁺: 354.1, (M−1)⁻: 352.2.

Cpd. 5

¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (t, J=5.6 Hz, 1H), 8.05 (s, 1H), 7.99(dd, J₁=6.0 Hz, J₂=2.0 Hz, 1H), 7.91 (dd, J₁=6.4 Hz, J₂=2.0 Hz, 1H),7.65 (d, J=8.8 Hz, 2H), 7.42 (m, 2H), 6.88 (d, J=8.4 Hz, 2H), 4.06 (t,J=6.0 Hz, 2H), 3.43 (pseudo q, J=5.6 Hz, 2H), 2.00 (pseudo p, J=6.0 Hz,2H). EM (calc.): 370.1; MS (ESI) m/e (M+1H)⁺: 371.1, (M−1H)⁻: 369.0.

Cpd. 6

¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.74 (t, J=6.0 Hz, 1H), 7.67(d, J=7.6 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.55 (dd,J₁=8.4 Hz, J₂=0.8 Hz, 1H), 7.43 (d, J=0.8 Hz, 1H), 7.37 (td, J₁=7.2 Hz,J₂=1.2 Hz, 1H), 7.241 (td, J₁=8.0 Hz, J₂=0.8 Hz, 1H), 6.89 (d, J=8.8 Hz,2H), 4.01 (t, J=6.4 Hz, 2H), 3.37 (pseudo q, J=6.0 Hz, 2H), 1.94 (pseudop, J=6.0 Hz, 2H). EM (calc.): 354.1; MS (ESI) m/e (M+1H)⁺: 355.2,(M−1H)⁻: 353.1.

Cpd. 7

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.65 (br d,J=7.2 Hz, 1H), 8.20 (s, 1H), 8.03 (m, 1H), 7.95 (m, 1H), 7.72 (d, J=8.4Hz, 2H), 7.46 (m, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.20 (m, 3H), 2.08 (m,1H), 1.02 (d, J=6.8 Hz, 6H). EM (calc.): 398.1; MS (ESI) m/e (M+1H)⁺:399.0, (M−1H)⁻: 397.1.

Cpd. 8

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.68 (d, J=8.0Hz, 1H), 8.17 (s, 1H), 8.03 (dd, J₁=2.0 Hz, J₂=6.4 Hz, 1H), 7.96 (dd,J₁=4.0 Hz, J₂=6.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.46 (m, 4H), 7.04(d, J=9.2 Hz, 2H), 4.24 (m, 1H), 4.18 (dd, J₁=6.8 Hz, J₂=10.0 Hz, 1H),4.09 (dd, J₁=5.2 Hz, J₂=9.6 Hz), 1.81 (m, 1H), 1.67 (m, 1H), 0.99 (t,J=7.6 Hz, 3H). EM (calc.): 384.1; MS (ESI) m/e (M+1H)⁺: 385.0, (M−1H)⁻:383.1.

Cpd. 9

¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.95 (br s, 1H), 8.80 (d,J=8.0 Hz, 1H), 8.19 (s, 1H), 8.06 (dd, J₁=5.6 Hz, J₂=1.6 Hz, 1H), 7.98(dd, J₁=6.8 Hz, J₂=1.6 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.49 (m, 2H),7.08 (d, J=8.8 Hz, 2H), 4.42 (p, J=6.4 Hz, 1H), 4.20 (dd, J₁=9.6 Hz,J₂=6.4 Hz, 1H), 4.07 (dd, J₁=9.6 Hz, J₂=5.6 Hz, 1H), 1.36 (d, J=6.8 Hz,3H). EM (calc.): 370.1; MS (ESI) m/e (M+1H)⁺: 371.0, (M−1H)⁻: 368.9.

Cpd. 10

¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H0, 8.65 (d, J=7.6 Hz, 1H), 8.04(s, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.83 (d, J=6.4 Hz, 1H), 7.61 (d, J=8.8Hz, 2H), 7.34 (m, 2H), 6.93 (d, J=8.8 Hz, 2H), 4.27 (p. J=6.4 Hz, 1H),4.05 (dd, J₁=6.8 Hz, J₂=10.0 Hz, 1H), 3.92 (dd, J₁=10.0 Hz, J₂=6.0 Hz,1H), 1.21 (d, J=5.2 Hz, 3H). EM (calc.): 370.1; MS (ESI) m/e (M+1H)⁺:370.9, (M−1H)⁻: 369.0.

Cpd. 11

¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.68(d, J=7.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.48(d, J=0.8 Hz, 1H), 7.38 (td, J₁=8.0 Hz, J₂=0.8 Hz, 1H), 7.25 (td, J₁=7.2Hz, J₂=0.8 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 4.19 (m, 1H), 4.07 (dd,J₁=10.4 Hz, J₂=6.4 Hz, 1H), 3.99 (dd, J₁=10.0 Hz, J₂=5.6 Hz, 1H), 1.68(m, 1H), 1.55 (m, 1H), 0.86 (t, J=7.2 Hz, 3H). EM (calc.): 368.1; MS(ESI) m/e (M−1H)⁻: 367.1.

Cpd. 12

¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 9.03 (t, J=6.0 Hz, 1H), 8.11(s, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.94 (d, J=6.4 Hz, 1H), 7.72 (d, J=8.8Hz, 2H), 7.46 (m, 2H), 7.07 (d, J=9.2 Hz, 2H), 4.72 (pseudo q, J=5.6 Hz,1H), 3.62 (m, 1H), 3.42 (m, 1H), 1.34 (d, J=6.4 Hz, 3H). EM (calc.):370.1; MS (ESI) m/e (M+1H)⁺: 371.0, (M−1H)⁻: 369.1.

Cpd. 13

¹H NMR (400 MHz, DMSO-14) δ 11.06 (s, 1H), 9.03, (t, J=5.6 Hz, 1H), 8.11(s, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.72 (d, J=8.4Hz, 2H), 7.46 (pseudo p, J=5.6 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 4.74(pseudo q, J=5.6 Hz, 1H), 3.63 (m, 1H), 3.42 (m, 1H), 1.34 (d, J=6.0 Hz,3H). EM (calc.): 370.1; MS (ESI) m/e (M+1H)⁺: 371.0, (M−1H)⁻: 369.1.

Cpd. 14

¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.92 (t, J=6.0 Hz, 1H), 7.75(d, J=7.6 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.54 (d, J=0.8 Hz, 1H), 7.44(td, J₁=7.2 Hz, J₂=0.8 Hz, 1H), 7.31 (td, J₁=7.6 Hz, J₂=0.8 Hz, 1H),7.03 (d, J=9.2 Hz, 2H), 4.69 (pseudo q, J=6.4 Hz, 1H), 3.59 (ddd, J₁=6.4Hz, J₂=13.6 Hz, J₃=19.6 Hz, 1H), 3.39 (ddd, J₁=6.0 Hz, J₂=12.4 Hz,J₃=19.6 Hz, 1H), 1.29 (d, J=6.4 Hz, 3H). EM (calc.): 354.1; MS (ESI) m/c(M+1H)⁺: 354.7, (M−1H)⁻: 353.1.

Cpd. 15

EM (calc.): 386.09; MS (ESI) m/c (M−1H)⁻: 384.7.

Cpd. 16

EM (calc.): 370.10; MS (ESI) m/e (M−1H)⁻: 369.0.

Cpd. 17

EM (calc.): 390.0; MS (ESI) m/c (M+1H)⁺: 391.2.

Cpd. 18

EM (calc.): 354.12; MS (ESI) m/e (M−1H)⁻: 353.2.

Cpd. 19

EM (calc.): 354.12; MS (ESI) m/e (M−1H)⁻: 353.1.

Cpd. 20

EM (calc.): 424.07; MS (ESI) m/e (M−1H)⁻: 423.9.

Cpd. 21

EM (calc.): 374.0; MS (ESI) m/e (M+1)⁺: 375.0, (M−1)⁻: 373.0.

Cpd. 22

EM (calc.): 386.1; MS (ESI) m/e (M+1)⁺: 387.1, (M−1)⁻: 384.7.

Cpd. 23

EM (calc.): 374.1; MS (ESI) m/e (M+1)⁺: 374.9, (M−1)⁻: 372.9.

Cpd. 24

EM (calc.): 370.1; MS (ESI) m/e (M+1)⁺: 370.8, (M−1)⁻: 369.0.

Cpd. 25

EM (calc.): 370.1; MS (ESI) m/e (M+1)⁺: 371.0, (M−1)⁻: 369.1.

Cpd. 26

EM (calc.): 414.14; MS (ESI) m/e (M+1H)⁺: 415.2, (M−1H)⁻: 413.2.

Cpd. 27

EM (calc.): 469.18; MS (ESI) m/e (M+1H)⁺: 470.1, (M−1H)⁻: 468.4.

Cpd. 28

EM (calc.): 447.14; MS (ESI) m/e (M+1H)⁺: 448.1, (M−1H)⁻: 446.2.

Cpd. 29

EM (calc.): 354.1; MS (ESI) m/e (M+1)⁺: 355.1, (M−1)⁻: 353.1.

Cpd. 30

EM (calc.): 370.1; MS (ESI) m/e (M+1)⁺: 371.0, (M−1)⁻: 368.9.

Cpd. 31

EM (calc.): 400.1; MS (ESI) m/e (M+1H)⁺: 401.0, (M−1H)⁻: 399.2.

Cpd. 32

EM (calc.): 427.1; MS (ESI) m/e (M+1H)⁺: 428.2, (M−1H)⁻: 426.2.

Cpd. 33

EM (calc.): 414.1; MS (ESI) m/e (M+1)⁺: 415.4, (M−1)⁻: 413.2;

Cpd. 34

EM (calc.): 469.2; MS (ESI) m/e (M+1)⁺: 470.1, (M−1)⁻: 468.3.

Cpd. 35

EM (calc.): 447.1; MS (ESI) m/e (M+1)⁺: 448.2, (M−1)⁻: 446.5.

Cpd. 36

EM (calc.): 368.1; MS (ESI) m/e (M+1)⁺: 369.0, (M−1)⁻: 367.2.

Cpd. 37

¹H NMR (400 MHz, DMSO-d₆) δ 11.69 (s, 1H), 11.04 (s, 1H), 8.77 (t, J=5.6Hz, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.39 (m, 2H), 7.11 (s, 1H), 7.05 (m,1H), 7.01 (d, J=8.4 Hz, 2H), 4.18 (t, J=6.0 Hz, 2H), 3.67 (m, 2H). EM(calc.): 357.1; MS (ESI) m/e (M+1H)⁺: 357.8, (M−1H)⁻: 356.2.

Cpd. 38

¹H NMR (400 Hz, DMSO-d₆) δ 11.42 (s, 1H), 11.05 (s, 1R), 8.66, (t, J=5.6Hz, 1H), 7.70 (d, J=9.2 Hz, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.03 (m, 4H),6.81 (m, 1H), 4.17 (t, J=5.6 Hz, 2H), 3.75 (s, 3H), 3.66 (m, 2H). EM(calc.): 369.1; MS (ESI) m/e (M+1H)⁻: 369.9, (M−1H)⁻: 368.2.

Cpd. 39

EM (calc.): 384.13; MS (ESI) m/e (M+1H)⁺: 384.9, (M−1H)⁻: 383.2.

Cpd. 40

EM (calc.): 446.15; MS (ESI) m/e (M+1H)⁺: 447.2, (M−1H)⁻: 445.4.

Cpd. 41

¹H NMR (400 MHz, DMSO-d₆) δ 11.28 (s, 1H), 11.04 (s, 1H), 8.53 (t, J=5.6Hz, 1H), 7.70 (d, J=9.2 Hz, 2H), 7.02 (m, 4H), 6.86 (s, 1H), 4.16 (t,J=5.6 Hz, 2H), 3.76 (s, 3H), 3.75 (s, 3H), 3.63 (m, 2H). EM (calc.):399.1; MS (ESI) m/e (M+1H)⁺: 400.0, (M−1H)⁻: 398.1.

Cpd. 42

¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (bs, 1H), 10.60 (bs, 1H), 9.29 (t,J=6.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.70 (m, 3H), 7.57 (t, J=7.2 Hz,1H), 7.45 (t, J=7.2 Hz, 1H), 7.00 (d, J=9.2 Hz, 2H), 4.83 (m, 2H), 4.23(t, J=6.0 Hz, 2H), 3.94 (m, 2H), 3.73 (m, 4H), 3.44 (m, 2H), 3.27 (m,2H). EM (calc.): 439.2; MS (ESI) m/e (M+1H)⁺: 439.8, (M−1H)⁻: 438.2.

Cpd. 44

EM (calc.): 412.16; MS (ESI) m/e (M+1H)⁺: 413.1, (M−1H)⁻: 411.3.

Cpd. 45

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.92 (t, J=5.2 Hz, 1H), 7.74(d, J=7.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.59 (s, 1H), 7.55 (d, J=6.8Hz, 1H), 7.32 (m, 3H), 7.06 (d, J=7.6 Hz, 2H), 7.00 (d, J=9.2 Hz, 2H),6.95 (t, J=7.2 Hz, 1H), 5.44 (s, 2H), 4.19 (t, J=6.0 Hz, 2H), 3.69 (m,2H). EM (calc.): 446.2; MS (ESI) m/e (M+1H)⁺: 447.2, (M−1H)⁻: 445.3.

Cpd. 46

¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.91 (t, J=5.6 Hz, 1H), 7.71(m, 3H), 7.58 (s, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H),7.03 (d, J=8.8 Hz, 2H), 4.78 (s, 2H), 4.20 (t, J=6.0 Hz, 2H), 3.69 (m,2H), 3.36 (s, 3H). EM (calc.): 384.1; MS (ESI) m/e (M+1H)⁺: 385.9,(M−1H)⁻: 383.2.

Cpd. 47

¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 11.09 (s, 1H), 9.32 (t, J=5.6Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.71 (m, 3H), 7.61 (s, 1H), 7.43 (t,J=7.6 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.68 (s, 2H), 4.23 (t, J=5.6 Hz,2H), 3.83 (m, 6H), 3.37 (m, 2H), 3.20 (m, 2H). EM (calc.): 439.2; MS(ESI) m/e (M+1H)⁺: 440.2, (M−1)⁻: 438.4.

Cpd. 48

¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H) 10.74 (s, 1H), 9.31 (t, J=5.6Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.65 (d, J=7.2Hz, 1H), 7.62 (s, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H),4.63 (d, J=5.2 Hz, 2H), 4.23 (t, J=6.0 Hz, 2H), 3.70 (m, 2H), 2.78 (s,3H), 2.770 (s, 3H). EM (calc.): 397.2; MS (ESI) m/e (M+1H)⁺: 398.0,(M−1H)⁻: 396.1.

Cpd. 49

EM (calc.): 384.1; MS (ESI) m/e (M−1)⁻: 382.9.

Cpd. 50

EM (calc.): 400.1; MS (ESI) m/e (M−1)⁻: 398.7.

Cpd. 51

1H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.78 (t, J=6.0 Hz, 1H), 7.71(m, 3H), 7.54 (s, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H),6.99 (d, J=8.4 Hz, 2H), 4.77 (s, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.47 (m,2H), 3.36 (s, 3H), 2.02 (m, 2H). EM (calc.): 398.2; MS (ESI) m/e(M+1H)⁺: 399.1, (M−1H)⁻: 397.1.

Cpd. 52

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (t, J=5.6 Hz, 1H), 7.71 (m, 3H), 7.54(m, 2H), 7.31 (m, 3H), 7.06 (d, J=8.0 Hz, 2H), 6.95 (m, 3H), 5.43 (s,2H), 4.09 (t, J=6.0 Hz, 2H), 3.47 (m, 2H), 2.02 (m, 2H). EM (calc.):460.2; MS (ESI) m/e (M+1H)⁺: 461.0, (M−1H)⁻: 459.1.

Cpd. 53

EM (calc.): 428.16; MS (ESI) m/e (M+1H)⁺: 428.9, (M−1H)⁻: 427.1.

Cpd. 54

¹H NMR (DMSO-d₆): 2.11 (3H, s); 2.78 (1H, dd, 14.8 Hz); 2.86 (1H, dd,14.5 Hz); 4.17 (1H, dd, 10.4 Hz); 4.23 (1H, dd, 10.6 Hz); 4.49 (1H, m);7.00 (2H, d, 9 Hz); 7.32 (1H, t, 7 Hz); 7.46 (1H, td, 8.1 Hz); 7.56 (1H,s); 7.64 (1H, d, 8 Hz); 7.70 (2H, d, 9 Hz); 7.77 (1H, d, 8 Hz); 8.77(1H, d, 8 Hz); 8.88 (1H, s). MS (M+1): 401.

Cpd. 55

¹H NMR (DMSO-d₆): 3.31 (3H, s); 3.53 (1H, dd, 13, 3.5 Hz); 3.66 (1H, dd,13.8 Hz); 4.16 (1H, dd, 9.6 Hz); 4.24 (1H, dd, 9.8 Hz); 4.87 (1H, m);7.00 (2H, d, 9 Hz); 7.33 (1H, t, 7 Hz); 7.47 (1H, t, 8 Hz); 7.57 (1H,s); 7.65 (1H, d, 8 Hz); 7.70 (2H, d, 9 Hz); 7.77 (1H, d, 8 Hz); 8.89(1H, s); 9.0 (1H, d, 8 Hz). MS (M−1): 431.

Cpd. 56

¹H NMR (400 MHz, DMSO-d₆) δ: 7.92 (br s, 1H), 8.76 (t, 1H, J=5.9 Hz),7.75 (m, 3H), 7.60 (d, 1H, J=7.6 Hz), 7.48 (t, 1H, J=8.0 Hz), 7.32 (t,1H, J=8.0 Hz), 7.27 (m, 5H), 7.17 (m, 1H), 7.04 (m, 2H), 4.21 (t, 2H,J=5.9 Hz), 3.69 (m, 2H) 3.39 (m, 2H), 2.96 (t, 2H, J=8.3 Hz). EM(calc.): 444; MS ESI) m/e (M+1H)⁺: 445.3, (M−1H)⁻: 443.3.

Cpd. 57

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 9.38 (s, 1H), 8.90 (s, 1H),7.94 (d, J=8.0 Hz, 1H), 7.57 (m, 10H), 6.97 (d, J=8.0 Hz, 2H), 4.80 (m,2H), 4.20 (s, 2H), 3.70 (m, 2H), 3.31 (m, 3H), 2.66 (m, 2H). MS ESI)m/e: (M+1H)⁺: 474.4, (M−1H)⁻: 472.1.

Cod. 58

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.73 (m, 1H), 8.89 (s, 1H),7.75 (d, J=8.0 Hz, 2H), 7.70 (t, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H),7.43 (t, 8.0 Hz, 1H), 7.18 (m, 6H), 6.98 (d, J=8.0 Hz, 2H), 4.13 (t,J=8.0 Hz, 2H), 3.95 (m, 2H), 3.58 (m, 2H), 2.78 (m, 2H), 2.65 (m, 2H),1.24 (s, 3H). MS ESI) m/e: (M+1H)⁺: 487.9, (M−1H)⁻: 486.1.

Cpd. 59

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.88 (s, 1H), 8.84 (t, J=8.0Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0Hz, 2H), 4.31 (s, 2H), 4.18 (t, J=8.0 Hz, 2H), 3.66 (m, 2H), 3.38 (m,2H), 2.45 (t, J=8.0 Hz, 2H), 1.65 (m, 2H). MS ESI) m/e: (M+1H)⁺: 445.2,(M−1H)⁻: 443.1.

Cpd. 60

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.04 (t, J=8.0 Hz, 1H), 7.86(d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.50(t, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 2H), 4.57(m, 2H), 4.18 (t, J=8.0 Hz, 2H), 3.65 (m, 2H), 3.46 (t, J=8.0 Hz, 2H),2.77 (m, 2H), 1.80 (m, 21. MS (ESI) m/e: (M+1H)⁺: 461.0, (M−1H)⁻: 459.1.

Cpd. 61

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.05 (t, J=8.0 Hz, 1H), 7.87(d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.51(t, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 2H), 5.11(s, 2H), 4.19 (t, J=8.0 Hz, 2H), 3.68 (m, 2H), 3.44 (t, J=8.0 Hz, 2H),3.13 (m, 2H), 1.83 (m, 2H). MS (ESI) m/e: (M+1H)⁺: 477.0, (M−1H)⁻:475.0.

Cpd. 62

MS (ESI) m/e: (M+1H)⁺: 527.6, (M−1)⁻: 525.5.

Cpd. 63

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 8.88 (br s, 1H), 8.73 (t,1H, J=5.9 Hz), 7.75-7.69 (m, 3H), 7.57-7.42 (m, 6H), 7.28 (t, 1H, J=7.7Hz), 7.00 (d, 2H, J=8.7 Hz), 4.17 (t, 2H, J=5.9 Hz), 3.65 (q, 2H, J=5.9Hz) 3.40 (t, 2H, J=6.9 Hz), 3.04 (t, 2H, J=6.9 Hz). EM (calc.): 512; MS(ESI) m/e (M+1H)⁺: 513.3, (M−1H)⁻: 511.2.

Cpd. 64

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 8.87 (br s, 1H), 8.83 (t,1H, J=5.9 Hz), 7.70 (m, 3H), 7.55 (d, 1H, J=8.3 Hz), 7.43 (t, 1H, J=7.4Hz), 7.34 (t, 1H, J=8.0 Hz), 7.28-7.20 (m, 3H), 7.11 (d, 1H, 8.0 Hz),7.00 (d, 2H, J=8.6 Hz), 4.17 (t, 2H, J=5.9 Hz), 3.65 (q, 2H, J=5.9 Hz)3.38 (t, 2H, J=8.3 Hz), 3.00 (t, 2H, J=8.3 Hz). EM (calc.): 528; MS(ESI) m/e (M+1H)⁺: 529.4, (M−1H)⁻: 527.5.

Cpd. 65

1H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 10.93 (s, 1H), 9.32 (m, 2H),9.23 (s, 1H), 8.89 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.70 (m, 3H), 7.56(t, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 2H), 4.64(s, 2H), 4.23 (t, J=8.0 Hz, 2H), 3.71 (m, 4H). MS (ESI) m/e: (M+1H)⁺:443.4, (M−1H)⁻: 441.4.

Cpd. 66

¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 9.33 (t, J=8.0 Hz, 1H), 8.89(s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.71 (m, 3H), 7.56 (t, J=8.0 Hz, 1H),7.43 (t, J=8.0 Hz, 3H), 7.00 (d, J=8.0 Hz, 2H), 4.60 (s, 2H), 4.23 (t,J=8.0 Hz, 2H), 3.71 (m, 2H), 3.20 (t, J=8.0 Hz, 2H), 2.72 (t, J=8.0 Hz,2H). MS (ESI) m/e: (M+1H)⁺: 442.3, (M−1H)⁻: 440.1.

Cpd. 67

¹H NMR (400 MHz, DMSO-d₆) δ: 9.11 (t, 1H, J=6.0 Hz), 7.82 (d, 1H, J=7.7Hz), 7.76 (d, 2H, J=8.5 Hz), 7.69 (d, 1H, J=8.5 Hz), 7.62 (s, 1H), 7.51(t, 1H, J=8.5 Hz), 7.40-7.30 (m, 3H), 7.21 (d, 2H, J=8.5 Hz), 7.00-6.97(m, 3H), 4.99 (m, 1H), 4.35 (m, 1H), 4.27 (m, 1H), 3.78 (m, 1H), 3.70(m, 1H). EM (calc.): 446.15; MS (ESI) m/e (M+1H)⁺: 447.4, (M−1H)⁻:445.3.

Cpd. 68

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.86 (t, J=4.0 Hz, 1H), 7.83(d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.47(t, J=8.0 Hz, 1H), 7.33 (t, J=4.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 2H), 5.02(s, 2H), 4.18 (t, J=8.0 Hz, 2H), 3.65 (m, 2H), 3.52 (t, J=8.0 Hz, 2H),3.44 (t, J=8.0 Hz, 2H), 1.68 (m, 2H). MS (ESI) m/e: (M+1H)⁺: 429.1,(M−1H)⁻: 426.9.

Cpd. 69

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 9.03 (t, 1H, J=5.9 Hz), 7.86(d, 1H, J=9.2 Hz), 7.70 (d, 2H, J=8.3 Hz), 7.63 (d, 1H, J=8.3 Hz), 7.49(t, 1H, J=8.8 Hz), 7.36 (t, 1H, J=7.0 Hz), 7.29 (t, 1H, J=8.8 Hz), 7.18(m, 1H), 7.07 (t, 1H, J=7.0 Hz), 7.00 (d, 1H, J=8.3 Hz), 6.91 (m, 1H),5.78 (s, 2H), 4.20 (t, 2H, J=5.9 Hz), 3.68 (q, 2H, J=5.9 Hz). EM(calc.): 464; MS (ESI) m/e (M+1H)⁺: 465.1, (M−1H)⁻: 463.1.

Cpd. 70

1H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 9.04 (t, 1H, J=5.9 Hz), 9.00(br s, 1H), 7.84 (d, 1H, J=7.3 Hz), 7.70 (d, 2H, J=9.2 Hz), 7.63 (d, 1H,J=8.1 Hz), 7.49 (t, 1H, J=8.6 Hz), 7.35 (t, 1H, J=7.7 Hz), 7.27 (m, 1H),7.18 (m, 1H), 7.00 (d, 1H, J=9.2 Hz), 6.95 (m, 1H), 6.87 (m, 1H), 6.74(m, 1H), 5.71 (s, 2H), 4.21 (t, 2H, J=5.9 Hz), 3.69 (q, 2H, J=5.9 Hz).EM (calc.): 464; MS (ESI) m/e (M+1H)⁺: 465.0, (M−1H)⁻: 463.1.

Cpd. 71

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 9.00 (t, 1H, J=5.9 Hz), 7.84(d, 1H, J=8.4 Hz), 7.70 (d, 2H, J=9.2 Hz), 7.62 (d, 1H, J=8.8 Hz), 7.48(t, 1H, J=8.4 Hz), 7.34 (t, 1H, J=7.3 Hz), 7.10-7.00 (m, 6H), 5.67 (s,2H), 4.20 (t, 2H, J=5.9 Hz), 3.68 (q, 2H, J=5.9 Hz). EM (calc.): 464; MS(ESI) m/c (M+1H)⁺: 464.9, (M−1H)⁻: 463.0.

Cpd. 72

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.88 (m, 2H), 7.86 (d, J=8.0Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0Hz, 1H), 7.33 (t, J=4.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 2H), 5.05 (s, 2H),4.19 (t, J=8.0 Hz, 2H), 3.65 (m, 2H), 3.59 (m, 2H), 3.47 (m, 2H), 3.23(s, 3H). MS (ESI) m/e: (M+1H)⁺: 428.9, (M−1H): 426.9.

Cpd. 73

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.20 (t, J=4.0 Hz, 1H), 8.83(d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.66(d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.25(d, J=8.0 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 6.07 (s, 2H), 4.21 (t, J=8.0Hz, 2H), 3.70 (m, 2H). MS ESI) m/e: (M+1H)⁺: 448.0, (M−1H)⁻: 446.4.

Cpd. 74

¹H NMR (400 MHz, DMSO-d₆): 8.86 (m, 1H), 8.81 (br s, 1H), 7.80 (d, 1H,J=8.2 Hz), 7.63 (d, 2H, J=9.4 Hz), 7.57 (d, 1H, J=8.2 Hz), 7.44 (t, 1H,J=7.8 Hz), 7.32 (t, 1H, J=7.0 Hz), 7.12 (t, 1H, J=9.0 Hz), 6.91 (t, 1H,J=8.6 Hz), 5.64 (s, 2H), 4.06 (t, 2H, J=6.0 Hz), 3.54 (t, 2H, J=6.0 Hz).EM (calc.): 500.13; MS (ESI) m/e (M+1H)⁺: 501.5, (M−1H)⁻: 499.3.

Cpd. 75

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.14 (t, J=4.0 Hz, 1H), 7.89(m, 1H), 7.70 (m, 3H), 7.61 (d, J=8.0 Hz, 1H), 7.46 (m, 1H), 7.40 (m,1H), 7.29 (t, J=4.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.43 (d, J=8.0 Hz,1H), 6.23 (t, J=4.0 Hz, 1H), 5.62 (s, 2H), 4.23 (t, J=4.0 Hz, 2H), 3.72(m, 2H). MS (ESI) m/e: (M+1H)⁺: 448.2, (M−1H)⁻: 446.4.

Cpd. 76

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.96 (1, J=4.0 Hz, 1H), 8.88(s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0Hz, 2H), 5.24 (s, 2H), 4.18 (m, 4H), 3.66 (m, 2H).

MS (ESI) m/e: (M+1H)⁺: 453.3, (M−1H)⁻: 451.1.

Cpd. 77

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.04 (t, J=4.0 Hz, 1H), 8.89(s, 1H), 8.09 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H),7.63 (d, J=8.0 Hz, 1H), 7.89 (m, 1H), 7.50 (m, 3H), 7.35 (t, J=8.0 Hz,1H), 7.17 (d, J=8.0 Hz, 2H), 7.03 (m, 3H), 5.77 (s, 2H), 4.22 (t, J=8.0Hz, 2H), 3.70 (m, 2H). MS (ESI) m/e: (M+1H)⁺: 513.1, (M−1H)⁻: 511.1.

Cpd. 78

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s, 1H), 8.97 (t, 1H, J=5.9 Hz), 8.81(s, 1H), 8.08 (s, 1H), 7.80 (d, 1H, J=7.6 Hz), 7.66-7.62 (m, 4H), 7.56(d, 1H, J=8.6 Hz), 7.42 (t, 1H, J=8.1 Hz), 7.28 (t, 1H, J=7.6 Hz), 7.15(m, 2H), 6.94 (d, 2H, J=8.6 Hz), 5.70 (s, 2H), 4.15 (t, 2H, J=5.9 Hz),3.64 (t, 2H, J=5.9 Hz). EM (calc.): 513.16; MS ESI) m/e (M+1H)⁺: 514.2,(M−1H)⁻: 512.2.

Cpd. 79

¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 10.33 (s, 1H), 9.25 (t, J=4.0Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.70 (m, 3H), 7.53 (t, J=8.0 Hz, 1H),7.44 (t, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 4.84 (d, J=4.0 Hz, 2H),4.23 (t, J=8.0 Hz, 2H), 3.70 (m, 2H), 3.48 (m, 2H), 3.23 (m, 2H), 2.04(m, 2H), 1.90 (m, 2H). MS ESI) m/e: (M+1H)⁺: 424.1, (M−1H)⁻: 422.3.

Cpd. 80

¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 9.87 (s, 1H), 9.29 (t, J=4.0Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.71 (m, 3H), 7.57 (t, J=8.0 Hz, 1H),7.45 (t, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 4.77 (s, 2H), 4.23 (t,J=8.0 Hz, 2H), 3.70 (m, 2H), 3.48 (m, 2H), 3.04 (m, 2H), 1.73 (m, 5H),1.38 (m, 1H). MS (ESI) m/e: (M+1H)⁺: 438.0, (M−1H)⁻: 436.3.

Cpd. 81

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.55 (t, J=4.0 Hz, 1H), 8.89(s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 6.99 (d, J=8.0Hz, 2H), 4.19 (t, J=8.0 Hz, 2H), 3.96 (s, 2H), 3.68 (m, 2H), 2.95 (m,2H), 2.28 (m, 1H), 2.09 (m, 2H), 1.78 (m, 2H), 1.44 (m, 2H). MS ESI)m/e: (M+1H)⁺: 506.1, (M−1H)⁻: 504.2.

Cpd. 82

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 9.18 (s, 1H), 8.04 (s, 1H),7.70 (m, 3H), 7.53 (t, J=8.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.00 (d,J=8.0 Hz, 2H), 4.21 (t, J=8.0 Hz, 2H), 3.70 (m, 12H), 2.76 (s, 3). MS(ESI) m/e: (M+1H)⁺: 453.0, (M−1H)⁻: 451.1.

Cpd. 83

¹H NMR (400 Hz, DMSO-d₆) δ 11.05 (s, 1H), 8.90 (m, 2H), 7.83 (d, J=8.0Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 2H), 5.08 (s, 2H),4.19 (t, J=8.0 Hz, 2H), 3.68 (m, 4H), 2.58 (m, 2H). MS ESI) m/e:(M+1H)⁺: 467.0, (M−1H)⁻: 465.1.

Cpd. 84

¹H NMR (400 MHz, DMSO-d₆) δ: 11.07 (s, 1H), 8.91 (m, 2H), 7.73 (d, 2H,J=9.0 Hz), 7.66 (s, 1H), 7.47 (d, 1H, J=8.7 Hz), 7.37 (t, 1H, J=8.4 Hz),7.15 (d, 1H, J=7.4 Hz), 7.04 (d, 2H, J=9.0 Hz), 4.21 (t, 1H, J=5.7 Hz),3.69 (t, 2H, J=5.7 Hz), 3.36 (s, 3H). EM (calc.): 354.12; MS (ESI) m/e(M+1H)⁺: 354.7, (M−1H)⁻: 353.1.

Cpd. 85

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.38 (s, 1H), 8.80 (t, J=8.0Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.32 (m, 3H), 7.03 (m, 4H), 4.76 (s,2H), 4.15 (t, J=8.0 Hz, 2H), 3.62 (m, 2H). MS ESI) m/e: (M+1H)⁺: 481.1,(M−1H)⁻: 479.0.

Cpd. 86

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.88 (m, 2H), 7.71 (d, J=8.0Hz, 2H), 7.55 (m, 4H), 7.46 (t, J=8.0 Hz, 1H), 7.28 (m, 3H), 7.00 (d,J=8.0 Hz, 2H), 4.77 (s, 2H), 4.15 (t, J=8.0 Hz, 2H), 3.60 (m, 2H). MS(ESI) m/e: (M+1H)⁺: 497.3, (M−1H)⁻: 495.1.

Cpd. 87

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.89 (s, 1H), 8.82 (t, J=8.0Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.63 (m, 3H),7.50 (t, J=8.0 Hz, 1H), 7.34 (m, 3H), 7.00 (d, J=8.0 Hz, 2H), 5.32 (s,2H), 4.06 (t, J=8.0 Hz, 2H), 3.49 (m, 2H). MS (ESI) m/e: (M+1H)⁺: 513.2,(M−1H)⁻: 511.2.

Cpd. 88

¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.88 (s, 1H), 8.68 (d, J=8.0Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.64 (d, J=8.0Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 6.98 (d, J=8.0Hz, 2H), 5.25 (s, 2H), 4.18 (m, 5H), 1.72 (m, 2H), 0.94 (t, J=8.0 Hz,3H). MS (ESI) m/e: (M+1H)⁺: 481.2, (M−1H)⁻: 479.2.

Cpd. 89

¹H NMR (400 MHz, DMSO-d₆) δ: 11.94 (s, 1H), 11.04 (m, 1H), 9.36 (m, 1H),8.88 (brs, 1H), 8.63 (s, 1H), 7.71 (d, 2H, J=8.5 Hz), 7.22 (t, 1H, J=8.1Hz), 7.07 (dd, 1H, J=8.1, 1.7 Hz), 7.02 (d, 2H, J=8.5 Hz), 6.65 (dd, 1H,J=7.6, 1.6 Hz), 4.21 (t, 2H, J=5.6 Hz), 3.73 (2H, q, J=5.2 Hz). EM(calc.): 356; MS (ESI) m/e (M+1H)⁺: 357.2, (M−1H)⁻: 354.9.

Cpd. 90

¹H NMR (400 MHz, DMSO-d₆) δ: 11.03 (s, 1H), 8.69 (d, 1H, J=8.3 Hz), 7.86(d, 1H, J=2.1 Hz), 7.69 (m, 3H), 7.54 (s, 1H), 7.47 (dd, 1H, J=8.5 Hz,2.5 Hz), 6.98 (d, 2H, J=8.6 Hz), 4.24 (m, 1H), 4.13 (m, 1H), 4.06 (m,1H), 1.75 (m, 1H), 1.62 (m, 1H), 0.93 (t, 3H, J=7.3 Hz). EM (calc.):402; MS (ESI) m/e (M+1H)⁺: 403.0, (M−1H)⁻: 400.9.

Cpd. 91

¹H NMR (400 MHz, DMSO-d₆) δ: 11.02 (s, 1H), 9.00 (t, 1H, J=5.8 Hz), 7.85(d, 1H, J=1.9 Hz), 7.68 (m, 3H), 7.52 (s, 1H), 7.46 (dd, 1H, J=8.5 Hz,1.9 Hz), 7.03 (d, 2H, J=8.5 Hz), 4.69 (m, 1H), 3.57 (m, 1H), 3.40 (m,1H), 1.32 (d, 3H, J=5.9 Hz). EM (calc.): 388; MS (ESI) m/e (M+1H)⁺:389.1, (M−1H)⁻: 387.0.

Cpd. 92

¹H NMR (400 MHz, DMSO-d₆) δ: 11.05 (br s, 1H), 8.96 (t, 1H, J=5.6 Hz),8.80 (d, 1H, J=2.0 Hz), 8.75 (dd, 1H, J=5.6, 0.8 Hz), 8.35, (d, 1H,J=8.0 Hz), 7.87 (dd, 1H, J=7.6, 5.6 Hz), 7.71 (m, 3H), 7.61 (d, 1H,J=8.0 Hz), 7.45 (t, 1H, J=6.8 Hz), 7.34 (d, 1H, J=7.2 Hz), 7.00 (m, 2H),4.91 (s, 2H), 4.75 (s, 2H), 4.18 (t, 2H, J=5.6 Hz), 3.66 (q, 2H, J=6.0Hz). EM (calc.): 461; MS ESI) m/e (M+1H)⁺: 462.2, (M−1H)⁻: 460.3.

Cpd. 93

¹H NMR (400 MHz, DMSO-d₆) δ: 11.00 (s, 1H), 8.82 (m, 1H), 8.37 (s, 1H),7.67 (dd, 2H, J=6.8, 1.6 Hz), 7.32-7.24 (m, 2H), 7.01 (d, 2H, J=9.6 Hz),6.90 (d, 1H, J=8.0 Hz), 4.17 (t, 2H, J=5.2 Hz), 3.89 (s, 3H), 3.69 (m,2H). EM (calc.): 370; MS (ESI) m/e (M+1H)⁺: 371.2, (M−1H)⁻: 369.1.

Cpd. 94

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 8.96 (t, 1H, J=5.6 Hz), 8.45(s, 1H), 7.70 (d, 2H, J=8.4 Hz), 7.37-7.30 (m, 2H), 7.02 (d, 2H, J=8.4Hz), 6.98 (dd, 1H, J=7.6, 0.8 Hz), 4.37 (m, 2H), 4.17 (t, 2H, J=5.6 Hz),3.82 (m, 2H), 3.69 (q, 2H, J=6.0 Hz), 3.34 (s, 3H). EM (calc.): 4.14; MSESI) m/e (M+1H)⁺: 415.2, (M−1H)⁻: 413.3.

Cpd. 95

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (br s, 1H), 8.86 (m, 1H), 8.65 (t,1H, 5.6 Hz), 8.61 (dd, 1H, J=4.8, 1.6 Hz), 8.37 (s, 1H), 8.13 (m, 1H),7.67 (m, 2H), 7.54 (m, 1H), 7.38-7.31 (m, 2H), 7.07 (dd, 1H, J=7.6, 0.8Hz), 6.88 (m, 2H), 5.40 (s, 2H), 3.91 (t, 2H, J=6.0 Hz), 3.40 (m, 2H).EM (calc.): 447; MS (ESI) m/e (M+1H)⁺: 448.2, (M−1H)⁻: 446.1.

Cpd. 96

¹H NMR (400 MHz, DMSO-d₆) δ: 11.57 (s, 1H), 8.65 (t, 1H, J=4.5 Hz), 7.69(d, 2H, J=8.5 Hz), 7.20 (s, 1H), 7.09-6.98 (m, 4H), 6.48 (d, 1H, J=7.9Hz), 4.17 (m, 2H), 3.85 (s, 3H), 3.65 (m, 2H). EM (calc.): 369; MS (ESI)m/e (M+1H)⁺: 370.1, (M−1H)⁻: 368.2.

Cpd. 97

¹H NMR (400 MHz, DMSO-d₆) δ: 11.06 (s, 1H), 8.62 (d, 1H, J=8.7 Hz), 7.88(d, 1H, J=7.6 Hz), 7.72 (d, 2H, J=8.5 Hz), 7.65 (d, 1H, J=8.5 Hz), 7.50(t, 1H, J=8.5 Hz), 7.36 (t, 1H, J=8.5 Hz), 7.02 (d, 2H, J=8.5 Hz), 5.08(s, 2H), 4.29 (m, 1H), 4.18 (m, 1H), 4.10 (m, 1H), 3.62 (m, 2H), 3.51(m, 2H), 3.26 (s, 3H), 1.77 (m, 1H), 1.67 (m, 1H), 0.97 (t, 3H, J=7.3Hz). EM (calc.): 456; MS (ESI) m/e (M+1H)⁺: 457.1, (M−1H)⁻: 455.2.

Cpd. 98

1H NMR (400 MHz, DMSO-d₆): 11.05 (s, 1H), 8.91 (t, 1H, J=6.1 Hz), 7.88(d, 1H, J=7.5 Hz), 7.72 (d, 2H, J=8.4 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.50(t, 1H, J=8.5 Hz), 7.36 (t, 1H, J=8.5 Hz), 7.07 (d, 2H, J=8.4 Hz), 5.07(s, 2H), 4.74 (q, 1H, J=6.0 Hz), 3.60 (m, 2H), 3.50 (m, 2H), 3.45 (m,2H), 3.26 (s, 3H), 1.32 (d, 3H, J=6.1 Hz). EM (calc.): 442; MS (ESI) m/e(M+1H)⁺: 443.1, (M−1H)⁻: 441.5.

Cpd. 99

¹H NMR (400 MHz, DMSO-d₆) δ: 11.09 (s, 1H), 9.54 (s, 1H), 9.40 (t, 1H,J=5.6 Hz), 8.04 (d, 1H, J=7.8 Hz), 7.74 (d, 2H, J=8.3 Hz), 7.61 (t, 1H,J=7.3 Hz), 7.49 (t, 1H, J=7.3 Hz), 7.03 (d, 2H, J=8.5 Hz), 4.82 (s, 2H),4.26 (t, 2H, J=5.6 Hz), 3.75 (q, 2H, J=5.6 Hz), 3.50 (m, 2H), 3.25 (m,4H), 1.32 (t, 6H, J=7.4 Hz). EM (calc.): 425; MS (ESI) m/e (M+1H)⁺:426.1, (M−1H)⁻: 424.2.

Cpd. 109

¹H NMR (DMSO-d₆): 1.95 (2H, m); 2.05 (3H, s); 2.48-2.62 (2H, m); 4.08(1H, dd, 11.6 Hz); 4.16 (1 h, dd, 11.7 Hz); 4.45 (1H, m); 6.99 (2H, d, 9Hz); 7.32 (1H, t, 7 Hz); 7.45 (1H, td, 8.1 Hz); 7.55 (1H, d, 1 Hz); 7.64(1H, d, 8 Hz); 7.69 (2H, d, 9 Hz); 7.76 (1H, d, 8 Hz); 8.7 (1H, d, 8Hz); 8.87 (1H, s). MS (M+1): 415.

Cpd. 110

¹H NMR (DMSO-d₆): 2.03-2.21 (2H, m); 2.99 (1H, s, 3H); 3.22 (2H, t, 7Hz); 4.12 (1H, dd, 11.6 Hz); 4.19 (th, dd, 11.7 Hz); 4.46 (1H, m); 7.00(2H, d, 9 Hz); 7.33 (1H, t, 7 Hz); 7.46 (1H, td, 8.1 Hz); 7.57 (1H, d, 1Hz); 7.64 (1H, d, 8 Hz); 7.70 (2H, d, 9 Hz); 7.77 (1H, d, 8 Hz); 8.79(1H, d, 8 Hz); 8.88 (1H, s). MS (M+1): 447.

Table 4:

Cpd. 1

EM (calc.): 381.13; MS (ESI) m/e (M+1H)⁺: 382.3, (M−1H): 380.2.

Cpd. 2

EM (calc.): 395.15; MS (ESI) m/e (M+1H)⁺: 396.1, (M−1H)⁻: 394.2.

Cpd. 3

EM (calc.): 331.08; MS (ESI) m/e (M+1H)⁺: 331.7, (M−1H)⁻: 330.1.

Cpd. 4

EM (calc.): 317.10; MS (ESI) m/e (M+1H)⁺: 318.10, (M−1H)⁻: 315.9.

Cpd. 5

EM (calc.): 425.2; MS (ESI) m/e (M+1)⁺: 426.1, (M−1)⁻: 424.1.

Cpd. 6

EM (calc.): 381.1; MS (ESI) m/e (M+1)⁺: 382.0, (M−1)⁻: 380.1.

Cpd. 7

EM (calc.): 381.1; MS (ESI) m/e (M+1)⁺: 382.0, (M−1)⁻: 380.2.

Cpd. 8

EM (calc.): 341.1; MS (ESI) m/e (M+1)⁺: 341.9, (M−1)⁻: 340.1.

Cpd. 9

EM (calc.): 381.1; MS (ESI) m/e (M+1)⁺: 381.8, (M−1)⁻: 380.0.

Cpd. 10

EM (calc.): 411.1; MS (ESI) m/e (M+1)⁺: 412.0, (M−1)⁻: 410.3.

Cpd. 11

EM (calc.): 395.2; MS (ESI) m/e (M+1)⁺: 396.0, (M−1)⁻: 394.2.

Cpd. 12

EM (calc.): 388.1; MS (ESI) m/e (M+1)⁺: 389.1, (M−1)⁻: 387.0.

Cpd. 13

EM (calc.): 355.12; MS (ESI) m/e (M+1)⁺: 355.9, (M−1)⁻: 354.1.

Cpd. 14

EM (calc.): 355.1; MS (ESI) m/e (M+1)⁺: 355.9, (M−1)⁻: 353.8.

Cpd. 15

EM (calc.): 409.2; MS (ESI) m/e (M+1)⁺: 410.2, (M−1)⁻: 408.3.

Cpd. 16

EM (calc.): 341.1; MS (ESI) m/e (M+1)⁺: 341.8, (M−1)⁻: 340.2.

Cpd. 17

¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 7.76(d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.46 (t, J=8.4Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 6.72 (s, 1H), 4.30 (m, 3H), 1.67 (m,2H), 0.92 (t, J=7.2 Hz, 3H). EM (calc.): 359.1; MS (ESI) m/e: (M+1H)⁺:359.8, (M−1H)⁻: 358.1.

Cpd. 18

¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 9.48 (s, 1H), 8.47 (d, J=8.0Hz, 1H), 8.09 (m, 1H), 7.82 (m, 2H), 7.71 (m, 2H), 7.55 (t, J=8.0 Hz,1H), 7.49 (m, 2H), 7.39 (m, 1H), 4.30 (m, 3H), 1.69 (m, 2H), 0.94 (t,J=7.2 Hz, 3H). EM (calc.): 395.2; MS (ESI) m/e: (M+1H)⁺: 395.8, (M−1H)⁻:394.0.

Cpd. 19

¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 8.93 (t, J=5.6 Hz, 1H), 7.75(d, J=7.6 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.45 (t, J=7.6Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.90 (m, 1H), 3.56 (m,2H), 0.35 (d, J=7.2 Hz, 3H). EM (calc.): 345.1; MS (ESI) m/e: (M+1H)⁺:345.8, (M−1H)⁻: 344.0.

Cpd. 20

¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 9.480 (s, 1H), 8.83 (t, J=5.6Hz, 1H), 7.07 (m, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H),7.53 (t, J=7.6 Hz, 1H), 7.48 (m, 2H), 7.39 (m, 1H), 6.72 (s, 1H), 4.91(m, 1H), 3.58 (m, 2H), 1.36 (d, J=7.0 Hz, 3H). EM (calc.): 381.1; MS(ESI) m/e: (M+H): 382.0, (M−1H)⁻: 380.0.

Cpd. 21

EM (calc.): 367.1; MS (ESI) m/c (M+1)⁺: 367.8, (M−1)⁻: 366.2.

Cpd. 22

EM (calc.): 367.12; MS (ESI) m/e (M+1H)⁺: 368.0, (M−1H)⁻: 366.1.

Cpd. 23

EM (calc.): 374.0; MS (ESI) m/e (M+1)⁺: 374.7, (M−1)⁻: 372.9.

Cpd. 24

EM (calc.): 395.2; MS (ESI) m/e (M+1)⁺: 396.1. (M−1)⁻: 394.1

Cpd. 25

EM (calc.): 367.1; MS (ESI) ml/e (M+1)⁺: 368.1, (M−1)⁻: 366.2.

Cpd. 26

EM (calc.): 381.1; MS (ESI) m/e (M+1)⁺: 382.0, (M−1)⁻: 380.1.

Cpd. 27

¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 9.45 (s, 1H), 8.54 (d, J=7.6Hz, 1H), 8.43 (s, 1H), 7.97 (m, 4H), 7.60 (m, 2H), 6.73 (s, 1H), 4.33(m, 3H), 1.70 (m, 2H), 0.96 (t, J=7.6 Hz, 3H). EM (calc.): 369.1; MS(ESI) m/e: (M+1H)⁺: 369.9, (M−1H)⁻: 368.0.

Cpd. 28

¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 9.50 (s, 1H), 8.53 (d, J=7.6Hz, 1H), 8.11 (m, 1H), 7.96 (m, 2H), 7.55 (m, 4H), 6.78 (s, 1H), 4.33(m, 3H), 1.68 (m, 2H), 1.01 (t, J=7.2 Hz, 3H). EM (calc.): 369.1; MS(ESI) m/e: (M+1H)⁺: 370.0, (M−1H)⁻: 368.2.

Cpd. 29

¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.86 (t, J=5.6 Hz, 1H), 8.40(s, 1H), 7.90 (m, 4H), 7.59 (m, 2H), 6.73 (s, 1H), 4.94 (m, 1H), 3.60(m, 2H), 1.38 (d, J=6.0 Hz, 3H). EM (calc.): 355.1; MS (ESI) m/e:(M+1H)⁺: 355.9, (M−1H)⁻: 353.9.

Cpd. 30

¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.78 (t, J=5.6 Hz, 1H), 8.09(d, J=7.6 Hz, 1H), 7.96 (m, 2H), 7.50 (m, 4H), 6.74 (s, 1H), 4.97 (m,1H), 3.61 (m, 2H), 1.41 (d, J=6.4 Hz, 3H). EM (calc.): 355.1; MS (ESI)m/e: (M+1H)⁺: 356.1, (M−1H)⁻: 353.9.

Cpd. 31

EM (calc.): 345.1; MS (ESI) m/e (M+1)⁺: 345.8, (M−1)⁻: 344.0.

Cpd. 32

EM (calc.): 331.1; MS (ESI) m/e (M+1)⁺: 331.9, (M−1)⁻: 330.2.

Cpd. 33

EM (calc.): 437.12; MS (ESI) m/e (M+1H)⁺: 438.0, (M−1H)⁻: 436.2.

Example 4 Synthesis of acetyl-Gly-Ala-(N-acetyl-Lys)-AMC

tert-Boc (N-Acetyl-Lys)-AMC (445 mg, 1 mmol, purchased from Bachem) wasdissolved in 4 M HCL in dioxane to provide H-(N-acetyl-Lys)-AMC as awhite solid. To a solution of H-(N-acetyl-Lys)-AMC in DMF (5 ml) wasadded Ac-Gly-Ala-OH (188 mg, 1 mmol) using PyBOP (520 mg, 1 mmol), HOBt(135 mg, 1 mmol), and NMM (0.296 ml, 2 mmol). The reaction mixture wasstirred for 1 h and monitored by MS/LC for the presence ofH-(N-acetyl-Lys)-AMC. Additional amounts of PyBOP (260 mg, 0.5 mmol),HOBt (70 mg, 0.5 mmol), and NMM (0.146 ml, 1 mmol) was added and thestirring was continued for additional 4 h after which the product wasisolated in quantitative yield.

Biological Examples Example 1 Inhibition of HDAC In Vitro

The HDAC inhibitory activity of the compounds of this invention in vitrowas determined as follows.

Measurements were performed in a reaction volume of 100 μL using 96-wellassay plates. HDAC-1 (200 μM final concentration) in reaction buffer (50mM HEPES, 100 mM KCl, 0.001% Tween-20, 5% DMSO, pH 7.4) was mixed withinhibitor at various concentrations and allowed to incubate for 30minutes, after which trypsin and acetyl-Gly-Ala-(N-acetyl-Lys)-AMC wereadded to final concentrations of 50 nM and 25 μM, respectively, toinitiate the reaction. Negative control reactions were performed in theabsence of inhibitor in replicates of eight.

The reactions were monitored in a fluorescence plate reader. After a 30minute lag time, the fluorescence was measured over a 30 minute timeframe using an excitation wavelength of 355 nm and a detectionwavelength of 460 nm. The increase in fluorescence with time was used asthe measure of the reaction rate. Inhibition constants were obtainedusing the program BatchKi (Kuzmic et al. Anal. Biochem. 2000, 286,45-50). Most of the compounds of this invention had a Ki of <40 nm.

Example 2 Cell Proliferation Assay In Vitro

The ability of the compounds of Formula (I) to inhibit growth of tumorcells in vitro was determined as follows.

Stock cultures of the HCT116 colon carcinoma cell line were maintainedin RPMI medium 1640 containing 10% (v/v) fetal bovine serum, 2 mML-glutamine, 1 mM sodium pyruvate, 50 units/ml penicillin, and 50 μg/mlstreptomycin at 37° C. in 5% CO₂ humidified atmosphere. Cells werecultured in 75-cm² culture flasks and subcultures were established every3 to 4 days so as not to allow the cells to exceed 90% confluence.

HCT116 cells were harvested for proliferation assays by trypsinization(0.05% trypsin/0.53 mM EDTA), washed twice in culture medium,re-suspended in appropriate volume of medium, and then counted using ahemacytometer. Cells were seeded in wells of flat-bottom 96-well platesat a density of 5,000 cell/well in 100 μl. Cells were allowed to attachfor 1.5 to 2 hours at 37° C.

Compounds were diluted from 10 mM stock solutions in DMSO. Serial 3-folddilutions were performed in medium containing 0.6% DMSO in wells (intriplicate) of a 96-well U-bottom plates starting with a 60 μM solution.After dilutions were completed, 100 μl of each compound dilution (intriplicate) was transferred to designated triplicate wells of the96-well plate containing cells in 100 μl of medium. Final concentrationsof the dose-response for compounds in assay plates ranged from 0.12 to30 μM. Control wells (cells with no treatment) received 100 μl of 0.6%DMSO in culture medium. Wells containing medium with no cells served asthe background wells. Cells were cultured with the compounds for 48 and72 hours at 37° C. in a humidified CO₂ incubator.

Cell proliferation was assessed by measuring fluorescence after theaddition of the fluorogenic redox indicator, Alamar Blue™ (BioSourceInternational). Ten μl of Alamar Blue™ was added to each well of the96-well plate(s) 3 to 4 hours prior to the end of the incubation period.Assay plates were read in a fluorescence plate reader (excitation, 530nM; emission, 620 nM). G_(I50) values (concentration at which the growthof the tumor cells was inhibited by 50%) for compounds were determinedby plotting the percent control fluorescence against the logarithm ofthe compound concentration. The compounds of this invention inhibitedthe growth of the tumor cells.

Pharmaceutical Composition Examples

The following are representative pharmaceutical formulations containinga compound of Formula (I)

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Quantity per Ingredient tablet, mg compound of this invention 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Quantity per Ingredient capsule, mg compound of this invention 200lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 gsodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 ggranulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K(Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilledwater q.s. to 100 ml

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention  1.2 g lactate buffersolution, 0.1M 10.0 ml HCl (1 N) or NaOH (1 N) q.s. to suitable pHsaline (optional) q.s. to suitable osmolarity water (distilled, sterile)q.s. to 20 ml

Compound (1.2 g) is combined with 0.1 M lactate buffer (10 ml) andgently mixed. Sonication can be applied for several minutes if necessaryto achieve a solution. Appropriate amount of acid or base is added q.s.to suitable pH (preferable pH 4). A sufficient amount of water is thenadded q.s. to 20 ml.

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing the compoundof the invention with Witepsol™ H-15 (triglycerides of saturatedvegetable fatty acid; Riches-Nelson, Inc., New York), and has thefollowing composition:

compound of the invention 500 mg Witepsol ™ H-15 balance

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled. All patents, patent applications andpublications cited in this application are hereby incorporated byreference in their entirety for all purposes to the same extent as ifeach individual patent, patent application or publication were soindividually denoted.

1. A compound of Formula (III):

wherein Ar is naphthyl; R¹ is hydrogen or alkyl; Y is alkyleneoptionally substituted with cycloalkyl, optionally substituted phenyl,alkylthio, alkylsulfinyl, alkysulfonyl, optionally substitutedphenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxyl,or optionally substituted phenoxy; R is one or two optional substituentsindependently selected from alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl,hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl,aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionallysubstituted phenyl, optionally substituted phenoxy, optionallysubstituted phenylalkyloxy, optionally substituted phenylalkyl,optionally substituted phenyloxyalkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyloxy, optionallysubstituted heteroaryloxyalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heterocycloalkyloxy,optionally substituted heterocycloalkylalkyloxy, -alkylene-S(O)_(n)R^(a)(where n is 0 to 2 and R^(a) is hydroxyalkyl or optionally substitutedphenyl), -alkylene-NR^(e)-alkyleneCONR^(c)R^(d), wherein R^(c) ishydroxyl and R^(d) and R^(e) are independently hydrogen or alkyl, orcarboxyalkylaminoalkyl; or a pharmaceutically acceptable salt thereof.2. The compound of claim 1 having the structure:


3. The compound of claim 1, wherein Y is —CH₂CH₂—.
 4. The compound ofclaim 2, wherein Y is —CH₂CH₂—.
 5. The compound of claim 1, wherein thenaphthyl group is monosubstituted.
 6. The compound of claim 2, whereinthe naphthyl group is monosubstituted.
 7. The compound of claim 5,wherein the substituent is N,N-dimethylaminomethyl,N,N-diethylaminomethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl,4-fluorophenoxymethyl, hydroxyl-4-yloxymethyl,2,4,6-trifluorophenoxy-methyl, 2-oxopyridin-1-ylmethyl,2,2,2-trifluoroethoxy-methyl, 4-imidazol-1-ylphenoxy-methyl,4-[1.2.4]-triazin-1-yl-phenoxymethyl, 2-phenylethyl,3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl,pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl,4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl,2-(3-trifluoromethoxyphenyl)ethyl, N-methyl-N-benzylaminomethyl,N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropyl-thiomethyl,3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonylmethyl,N-methyl-N-2-indol-3-ylethylaminomethyl,2-(4-trifluoromethylphenyl)ethyl,N-hydroxyaminocarbonyl-methylaminomethyl, or 2-carboxyethylaminomethyl.8. The compound of claim 6, wherein the substituent isN,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-fluorophenoxymethyl,3-fluorophenoxymethyl, 4-fluorophenoxymethyl, hydroxyl-4-yloxymethyl,2,4,6-trifluorophenoxy-methyl, 2-oxopyridin-1-ylmethyl,2,2,2-trifluoroethoxy-methyl, 4-imidazol-1-ylphenoxy-methyl,4-[1.2.4]-triazin-1-yl-phenoxymethyl, 2-phenylethyl,3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl,pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl,4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl,2-(3-trifluoromethoxyphenyl)ethyl, N-methyl-N-benzylaminomethyl,N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropyl-thiomethyl,3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonylmethyl,N-methyl-N-2-indol-3-ylethylaminomethyl,2-(4-trifluoromethylphenyl)ethyl,N-hydroxyaminocarbonyl-methylaminomethyl, or 2-carboxyethylaminomethyl.9. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 or pharmaceutically acceptable saltsthereof and a pharmaceutically acceptable excipient.
 10. Thepharmaceutical composition of claim 9 comprising a therapeuticallyeffective amount of a compound having the structure:

or pharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable excipient.